COVID-19: Extensive epithelial damage and ciliary dyskinesia in hospitalised patients.

Infection with SARS-CoV-2 can cause severe respiratory disease and it is predicted that the COVID-19 pandemic will leave a substantial number of patients with long-term respiratory complications (1).

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Hyperoxia for performance and training.

Recent technological developments have made it possible to use hyperoxia as an enhancement aid during training. Athletes wearing a mask can breathe a higher fraction of oxygen from a stationary or portable apparatus while exercising. A large body of evidence indicates that the oxygen transport capacity, lactate metabolism, power output and work tolerance (endurance) are improved when breathing hyperoxia. The physiological mechanisms underlying these performance improvements, although still not fully elucidated, are based on higher oxygen delivery and reduced central fatigue. Although much is known about the acute effects of hyperoxia, the effect of hyperoxic-supplemented endurance training on performance and the mechanisms beneath training adaptations are not very well understood, especially in well-trained endurance athletes. The few studies on the physiological effects of hyperoxia training have been conducted with conflicting results, discussed in this paper. Potential detrimental effects have not yet been shown experimentally and warrant further investigation.

Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines.

Cardiovascular (CV) toxicity is a potential short- or long-term complication of various anticancer therapies. Some drugs, such as anthracyclines or other biological agents, have been implicated in causing potentially irreversible clinically important cardiac dysfunction. Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy agents, rare but serious complications have been described, and longer follow-up is needed to determine the exact profile and outcomes of related cardiac side-effects. Some of these side-effects are irreversible, leading to progressive CV disease, and some others induce reversible dysfunction with no long-term cardiac damage to the patient. Assessment of the prevalence, type and severity of cardiac toxicity caused by various cancer treatments is a breakthrough topic for patient management. Guidelines for preventing, monitoring and treating cardiac side-effects are a major medical need. Efforts are needed to promote strategies for cardiac risk prevention, detection and management, avoiding unintended consequences that can impede development, regulatory approval and patient access to novel therapy. These new ESMO Clinical Practice Guidelines are the result of a multidisciplinary cardio-oncology review of current evidence with the ultimate goal of providing strict criteria-based recommendations on CV risk prevention, assessment, monitoring and management during anticancer treatment.

Assessment of cardiotoxicity with cardiac biomarkers in cancer patients.

Cardiotoxicity remains a major limitation of chemotherapy, strongly affecting the quality of life and the overall survival of cancer patients, regardless of their oncologic prognosis. The time elapsed from the end of cancer therapy to the beginning of heart failure therapy for chemotherapy-induced cardiac dysfunction is an important determinant of the extent of recovery. This highlights the need for a real-time diagnosis of cardiac injury. The current standard for monitoring cardiac function detects cardiotoxicity only when a functional impairment has already occurred, precluding any chance of preventing its development. In the last decade, early identification, assessment, and monitoring of cardiotoxicity, by measurement of serum cardiospecific biomarkers, have been proposed as an effective alternative. In particular, the role of troponin I in identifying patients at risk for cardiotoxicity and of angiotensin-converting enzyme inhibitors in preventing left ventricular ejection fraction reduction and cardiac events has clearly proved to be an effective strategy for this complication. In addition, novel biomarkers for the identification of cardiotoxicity are emerging. The use of a multimarker approach may provide a unique opportunity for advancement in this field, allowing for better stratification of the cardiac risk in cancer patients treated with anticancer drugs.

Influence of Hyperoxic-Supplemented High-Intensity Interval Training on Hemotological and Muscle Mitochondrial Adaptations in Trained Cyclists.

Background: Hyperoxia (HYPER) increases O2 carrying capacity resulting in a higher O2 delivery to the working muscles during exercise. Several lines of evidence indicate that lactate metabolism, power output, and endurance are improved by HYPER compared to normoxia (NORM). Since HYPER enables a higher exercise power output compared to NORM and considering the O2 delivery limitation at exercise intensities near to maximum, we hypothesized that hyperoxic-supplemented high-intensity interval training (HIIT) would upregulate muscle mitochondrial oxidative capacity and enhance endurance cycling performance compared to training in normoxia. Methods: 23 trained cyclists, age 35.3 ± 6.4 years, body mass 75.2 ± 9.6 kg, height 179.8 ± 7.9 m, and VO2max 4.5 ± 0.7 L min-1 performed 6 weeks polarized and periodized endurance training on a cycle ergometer consisting of supervised HIIT sessions 3 days/week and additional low-intensity training 2 days/week. Participants were randomly assigned to either HYPER (FIO2 0.30; n = 12) or NORM (FIO2 0.21; n = 11) breathing condition during HIIT. Mitochondrial respiration in permeabilized fibers and isolated mitochondria together with maximal and submaximal VO2, hematological parameters, and self-paced endurance cycling performance were tested pre- and posttraining intervention. Results: Hyperoxic training led to a small, non-significant change in performance compared to normoxic training (HYPER 6.0 ± 3.7%, NORM 2.4 ± 5.0%; p = 0.073, ES = 0.32). This small, beneficial effect on the self-paced endurance cycling performance was not explained by the change in VO2max (HYPER 1.1 ± 3.8%, NORM 0.0 ± 3.7%; p = 0.55, ES = 0.08), blood volume and hemoglobin mass, mitochondrial oxidative phosphorylation capacity (permeabilized fibers: HYPER 27.3 ± 46.0%, NORM 16.5 ± 49.1%; p = 0.37, ES = 3.24 and in isolated mitochondria: HYPER 26.1 ± 80.1%, NORM 15.9 ± 73.3%; p = 0.66, ES = 0.51), or markers of mitochondrial content which were similar between groups post intervention. Conclusions: This study showed that 6 weeks hyperoxic-supplemented HIIT led to marginal gain in cycle performance in already trained cyclists without change in VO2max, blood volume, hemoglobin mass, mitochondrial oxidative phosphorylation capacity, or exercise efficiency. The underlying mechanisms for the potentially meaningful performance effects of hyperoxia training remain unexplained and may raise ethical questions for elite sport.

Muscle mass and inspired oxygen influence oxygen extraction at maximal exercise: Role of mitochondrial oxygen affinity.

AIM: We examined the Fick components together with mitochondrial O2 affinity (p50mito ) in defining O2 extraction and O2 uptake during exercise with large and small muscle mass during normoxia (NORM) and hyperoxia (HYPER). METHODS: Seven individuals performed 2 incremental exercise tests to exhaustion on a bicycle ergometer (BIKE) and 2 on a 1-legged knee extension ergometer (KE) in NORM or HYPER. Leg blood flow and VO2 were determined by thermodilution and the Fick method. Maximal ADP-stimulated mitochondrial respiration (OXPHOS) and p50mito were measured ex vivo in isolated mitochondria. Mitochondrial excess capacity in the leg was determined from OXPHOS in permeabilized fibres and muscle mass measured with magnetic resonance imaging in relation to peak leg O2 delivery. RESULTS: The ex vivo p50mito increased from 0.06 ± 0.02 to 0.17 ± 0.04 kPa with varying substrate supply and O2 flux rates from 9.84 ± 2.91 to 16.34 ± 4.07 pmol O2 ·s-1 ·µg-1 respectively. O2 extraction decreased from 83% in BIKE to 67% in KE as a function of a higher O2 delivery and lower mitochondrial excess capacity. There was a significant relationship between O2 extraction and mitochondrial excess capacity and p50mito that was unrelated to blood flow and mean transit time. CONCLUSION: O2 extraction varies with mitochondrial respiration rate, p50mito and O2 delivery. Mitochondrial excess capacity maintains a low p50mito which enhances O2 diffusion from microvessels to mitochondria during exercise.

Optimizing clinical care of patients with metastatic breast cancer: a new oral vinorelbine plus trastuzumab combination.

BACKGROUND: Trastuzumab (T) combined with i.v. vinorelbine (i.v.VNR) is an active regimen for patients with advanced breast cancer (ABC). In order to further improve quality of life of patients undergoing treatment for ABC, a new regimen using oral vinorelbine (oVNR) (d1 + d3) plus q3wks T was tested (ToVNR). PATIENTS AND METHODS: Thirty-nine patients with ABC, human epidermal growth factor receptor 2/neu 3+ or FISH positive received 288 treatment cycles with T 6 mg/kg (loading dose, 8 mg/kg) on d1 and oVNR 55 mg/m(2) on d1 + d3, q3wks until disease progression or unacceptable toxicity. RESULTS: Thirty-seven patients and 286 treatment cycles were evaluated (two patients were lost to follow-up). Treatment was very well tolerated. Two patients had complete response (CR), 14 partial response (PR), 17 stable disease (SD) and four disease progression (PD) (overall response rate: 43%). Clinical benefit rate (CR + PR + SD >24 months) was 73%. Median time to progression was 8.9 months (range 2-27) and median duration of response was 10.9 months (range 2-27). CONCLUSIONS: The ToVNR combination is active and very well tolerated. It favorably compares with the combination of T and weekly i.v. administered VNR, allowing a more convenient once every three weeks hospital admission and leaving patients and care providers free from the unpleasant effect of i.v.VNR.

Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy.

OBJECTIVES: We investigated the role of cardiac troponin I (cTnI) in patients with aggressive malignancies treated with high-dose chemotherapy (HDC). BACKGROUND: High dose chemotherapy is potentially limited by cardiac toxicity. Considering the fact that cardiac dysfunction may become clinically evident weeks or months after HDC, the availability of an early marker of myocardial injury, able to predict late ventricular impairment, is a current need. METHODS: We measured, in 204 patients (45+/-10 years) affected by cancer resistant to conventional treatment, the cTnI plasma concentration after every single cycle of HDC. According to the cTnI value (< or = or >0.4 ng/ml), patients were divided into a troponin positive (cTnI+, n = 65) and a troponin negative (cTnI-, n = 139) group. All patients underwent echocardiographic examination during the following seven months. RESULTS: In the cTnI- group, left ventricular ejection fraction (LVEF) progressively decreased after HDC, reaching a maximal reduction after three months; however, myocardial depression was transient and no longer detectable at later follow-up. By contrast, in the cTnI+ group LVEF reduction was more marked and still evident at the end of the follow-up. In cTnI+ patients, a close relationship between the short-term cTnI increment and the greatest LVEF reduction was found (r = -0.87, p<0.0001). CONCLUSIONS: The elevation of cTnI in patients undergoing HDC for aggressive malignancies accurately predicts the development of future LVEF depression. In this setting, cTnI can be considered a sensitive and reliable marker of acute minor myocardial damage with relevant clinical and prognostic implications.

Usefulness of excitable gap and pattern of resetting in atrial flutter for determining reentry circuit location.

Clinical and experimental data show that type I atrial flutter is due to a reentry mechanism with an excitable gap. To define the location of the reentry circuit of atrial flutter, width of excitable gap, poststimulation cycle and pattern of reset after premature stimulus were analyzed in 18 patients during atrial flutter at multiple atrial sites (high, lateral, posterior and septal right atrium, and coronary sinus). The pattern of reset was defined as flat or increasing whether the return cycle remained unchanged or prolonged with increasing prematurity. Shorter values of the excitable gap were found at the coronary sinus (33 +/- 8 ms) and high right atrium (30 +/- 10 ms) than at the posterior (43 +/- 9 ms) or septal right atrium (45 +/- 11 ms). Intermediate values (36 +/- 8 ms) were measured at the lateral right atrium. Poststimulation cycle, corrected for atrial flutter cycle length, was shorter in the posterior (6 +/- 7 ms) and septal right atrium (5 +/- 7 ms) than in the coronary sinus (35 +/- 9 ms), and the high (23 +/- 10 ms) and lateral right atrium (15 +/- 9 ms). A flat pattern of resetting occurred more frequently at the septal (18 of 18 patients) and posterior right atrium (15 of 18) than at the lateral (8 of 18) and high right atrium (2 of 17), and was never observed at the coronary sinus. Atrial flutter was successfully terminated by overdrive atrial pacing in 15 of 18 patients, and termination was more easily obtained from the septal and posterior right atrium.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of acute toxicities associated with autologous peripheral blood progenitor cell reinfusion in patients undergoing high-dose chemotherapy.

Peripheral blood progenitor cell reinfusion (PBPC) in patients undergoing high-dose chemotherapy (HDC) for poor prognosis malignancies, has been described as causing possible acute gastrointestinal (nausea, vomiting), allergic (oedema, bronchospasm, anaphyl- axis), renal (proteinuria, haematuria) and/or cardiovascular (hypotension, arrhythmia, conduction disturbances, transient ischaemic phenomena) toxicities. To establish the clinical relevance of these observations and the possible relationship with different HDC regimens used, we performed a clinical and instrumental evaluation on 33 patients with advanced breast cancer, non-Hodgkin's lymphoma, Hodgkin's disease, relapsed ovarian cancer, Ewing's sarcoma, extragonadal germinal tumour and small cell lung cancer. They underwent at least one reinfusion each for a total of 51 studied procedures. No patient had a previous history of cardiovascular disease or significant intercurrent illness such as diabetes or liver, renal or neurologic impairment. All patients had totally implanted central venous catheters, through which the transplants had been collected and reinfused without technical consequences. To evaluate cardiovascular function, we continuously monitored 12-lead ECGs, with arterial pressure (AP) measurements every 5 min from the beginning of the procedure to 15 min after the reinfusion ended. We did not observe any significant differences between basal and subsequent steps in AP, heart rate, PQ and QTc time, P wave and QRS complex duration or P wave and QRS electrical axes. No patient showed any ST-T tract pathological abnormality, but one patient developed a transient ectopic atrial rhythm, without any haemodynamic disfunction and with spontaneous reversion to sinus rhythm. No patient complained of symptoms of haemodynamic failure. Gastrointestinal side-effects appeared to be strictly related to speed of reinfusion and to the number of packs reinfused, probably reflecting on the amount of dimethylsulphoxide infused. In one patient a tonic-clonic seizure occurred during a vomiting episode, but no patient developed allergic or renal toxicities. We conclude that PBPC reinfusion, if managed according to the procedure we propose in patients without organic impairment, is a safe procedure not associated either with increased risk of acute arrhythmias or ischaemic or significant systemic acute toxicities. Bone Marrow Transplantation (2000) 25, 173-177.

Atrial fibrillation after operation for lung cancer: clinical and prognostic significance.

BACKGROUND: Atrial fibrillation is a common complication of early postoperative period in lung cancer thoracotomy. Its clinical incidence and short- and long-term impact on overall mortality has never been definitely assessed; moreover, it is unclear whether the arrhythmia represents an independent cardiac risk factor. METHODS: We prospectively studied 233 consecutive patients undergoing operation for lung cancer (170 with non-small-cell lung cancer). Postoperative atrial fibrillation incidence was related to different clinical factors possibly involved in its occurrence and to both short- and long-term survival. RESULTS: Atrial fibrillation occurred in 28 patients (12%) (same percentage in non-small-cell lung cancer); a strong relationship was observed between arrhythmia and age, history of hypertension and associated lymph node resection. The mean hospitalization time was 14 +/- 4 days in patients developing atrial fibrillation and 13 +/- 4 days in those who did not (p = not significant). No difference was observed between the two groups with regard to short- or long-term mortality or to long-term atrial fibrillation recurrences, also when considering the entire population and only non-small-cell lung cancer, separately. CONCLUSIONS: At our institution, early atrial fibrillation occurrence after operation for lung cancer does not show any negative impact on short- and long-term mortality or on recurrence rate.

Design and characterization of a mutation outside the active site of human thymidylate synthase that affects ligand binding.

Owing to its central role in DNA synthesis, human thymidylate synthase (hTS) is a well-established target for chemotherapeutic agents, such as fluoropyrimidines. The use of hTS inhibitors in cancer therapy is limited by their toxicity and the development of cellular drug resistance. Here, with the aim of shedding light on the structural role of the A-helix in fluoropyrimidine resistance, we have created a fluoropyrimidine-resistant mutant by making a single point mutation, Glu30Trp. We postulated that residue 30, which is located in the A-helix, close to but outside the enzyme active site, could have a long-range effect on inhibitor binding. The mutant shows 100 times lower specific activity with respect to the wild-type hTS and is resistant to the classical inhibitor, FdUMP, as shown by a 6-fold higher inhibition constant. Circular dichroism experiments show that the mutant is folded. The results of molecular modeling and simulation suggest that the Glu30Trp mutation gives rise to resistance by altering the hydrogen-bond network between residue 30 and the active site.

Homodimeric enzymes as drug targets.

Many enzymes and proteins are regulated by their quaternary structure and/or by their association in homo- and/or hetero-oligomer complexes. Thus, these protein-protein interactions can be good targets for blocking or modulating protein function therapeutically. The large number of oligomeric structures in the Protein Data Bank (http://www.rcsb.org/) reflects growing interest in proteins that function as multimeric complexes. In this review, we consider the particular case of homodimeric enzymes as drug targets. There is intense interest in drugs that inhibit dimerization of a functionally obligate homodimeric enzyme. Because amino acid conservation within enzyme interfaces is often low compared to conservation in active sites, it may be easier to achieve drugs that target protein interfaces selectively and specifically. Two main types of dimerization inhibitors have been developed: peptides or peptidomimetics based on sequences involved in protein-protein interactions, and small molecules that act at hot spots in protein-protein interfaces. Examples include inhibitors of HIV protease and HIV integrase. Studying the mechanisms of action and locating the binding sites of such inhibitors requires different techniques for different proteins. For some enzymes, ligand binding is only detectable in vivo or after unfolding of the complexes. Here, we review the structural features of dimeric enzymes and give examples of inhibition through interference in dimer stability. Several techniques for studying these complex phenomena will be presented.

Long QT syndrome and torsade de pointes after anthracycline chemotherapy.

Anthracycline chemotherapy, which represents the treatment of choice for many hematologic and metastatic cancers, unfortunately carries with it the possibility of both early cardiotoxic phenomena, occuring during chemotherapy, and also late cardiotoxic manifestations, occuring even months or years from the completion of treatment.THE CLINICAL MANIFESTATIONS OF EARLY CARDIOTOXICITY COMMONLY INCLUDE: ventricular premature beats, supraventricular tachycardia, cardiomyopathy and sudden death.This study confirms the necessity for close cardiac monitoring of patients undergoing anthracycline therapy. Such monitoring should not only comprise echocardiographic monitoring for left ventricular systo-diastolic dysfunction, but also electrocardiographic monitoring (QTc) in order to exclude electrophysiological changes possibly related to life threatening arrhythmias (10).

QTc prolongation assessment in anticancer drug development: clinical and methodological issues.

Cardiac safety assessments are commonly employed in the clinical development of investigational oncology medications. In anti-cancer drug development there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can potentially influence decision making at many levels during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Given the potential for serious and irreversible morbidity from cardiac adverse events, it is understandable that cardiac safety results can have broad impact on study conduct and patient management. The methodologies for risk management of QTc prolongation for non cardiac drugs have been developed out of experiences primarily from drugs used to treat non life-threatening illnesses in a chronic setting such as antibiotics or antihistamines. Extrapolating these approaches to drugs for treating cancer over an acute period may not be appropriate. Few specific guidelines are available for risk management of cardiac safety in the development and use of oncology drugs. In this manuscript, clinical and methodological issues related to QTc prolongation assessment will be reviewed. Discussions about limitations in phase-I design and oncology drug development will be highlighted. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. A thoughtful risk management plan generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development programme essential for oncology agents with cardiac safety concerns.

Cardio-oncology: a new medical issue.

Due to the increasing number of long-term cancer survivors, the ageing of the population, as well as the increased incidence and prevalence of oncologic and cardiovascular diseases, the number of patients presenting oncologic and cardiologic co-morbidities are increasing. Accordingly, there is a rapidly growing need for a comprehensive and proficient management of patients in whom the two co-morbidities exist, and for cancer patients whose clinical history and oncologic treatment put them at higher risk for developing cardiovascular problems, in order to provide the optimal treatment in every situation, and to avoid the possibility that the development of the second disease does not lead to a reduction of therapeutic opportunities for the patient. A new discipline, cardio-oncology, has been created to deal with this need. Its aim is to investigate new strategies, collect new evidence-based indications and develop interdisciplinary expertise in order to manage this growing category of patients. Cardio-oncology deals with the following main clinical and research areas: early diagnosis of cardiotoxicity, risk stratification and preventions, treatment and monitoring of cardiotoxicity.

Intrapericardial treatment of neoplastic pericardial effusions.

Pericardial effusion and cardiac tamponade are known complications of many advanced malignancies as lung cancer, breast cancer, lymphomas and leukemias. Initial relief can be easily obtained with percutaneous echo-guided pericardiocentesis, without significant mortality and morbidity and well-tolerated even in critically ill patients. Effusion recurrences can be observed, however, in up to 40% of cases if only simple pericardial drainage is performed. Effective management can be obtained by instillation in the pericardial sac of different agents, with sclerosing or cytostatic activity, like tetracyclines, bleomycin, thiotepa or radionuclides. Intrapericardial sclerotherapy is associated to good results in terms of recurrence prevention and survival improvement. Absence of pericardial effusion at 30 days after drainage can be observed in 70 to 90% of all treated patients, without significant variations among different treatments. No significant side effects are observed, with the exclusion of chest pain during tetracyclines instillation. In our opinion pericardiocentesis associated to intrapericardial sclerotherapy with thiotepa is the best compromise in terms of recurrence prevention, tolerability and costs. Real randomized, case-control studies are moreover required to assess the gold standard of malignant pericardial effusions treatment.

[Neurohumoral changes induced by hemofiltration in congestive heart failure: physiopathological inferences]. / Modificazioni neuroumorali indotte dalla emofiltrazione nello scompenso congestizio: inferenze fisiopatologiche.

Hemofiltration is a method suitable for rapid substraction of plasma water that generally allows reduction of circulating levels of norepinephrine. Using that non-pharmacological approach we investigated the mechanisms involved in the metabolism of the hormone as well as the hemodynamic correlates of a prompt and great fall of the sympathetic neurotransmitter in patients with chronic refractory congestive heart failure (CHF). In 23 patients with CHF, hemofiltration of 2983 +/- 1228 ml of plasma water (in 5 +/- 2 hours of treatment) increased urinary output by 606 +/- 415 ml in the day of the procedure as well as sodium excretion by 53 +/- 38 mEq/24 h; simultaneously, a mean fall in plasma norepinephrine concentration by 515 +/- 444 pg/ml was observed. These effects were prompt and persisted or even rose in the next 24 and 48 hours, not being related to changes in plasma renin activity, right atrial, wedge pulmonary artery and renal perfusion pressures and to the amount and duration of hemofiltration. Our data did not clarify the mechanism involved in the increase of the diuresis and for its coupling with the fall in plasma norepinephrine. Nevertheless, we found a strong and statistically significant correlation (r = 0.7; p less than 0.01) between percent changes from baseline values of norepinephrine and diuresis. It is therefore suggested that the same, still unknown, mechanism which increased urinary output also potentiated norepinephrine removal by the kidney: or that water reabsorption from extravascular spaces (triggered by hemofiltration and continued by increased diuresis) resulted in regression of organ congestion leading to an improved clearance of norepinephrine by different organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy.

BACKGROUND: High-dose chemotherapy (HDC) has been widely utilized in high-risk breast cancer, but it may induce cardiac toxicity. Cardiac dysfunction may become evident weeks or months after HDC and, to date, no early markers of myocardial injury that are able to predict late ventricular impairment are available. We investigated the role of plasma troponin I (TnI) in this setting. PATIENTS AND METHODS: We measured TnI plasma concentration after HDC in 211 high-risk breast cancer women (46 +/- 11 years, mean +/- SD). According to TnI value (< 0.5 or > or = 0.5 ng/ml), patients were allocated into a troponin positive (TnI+; n = 70) and a troponin negative (TnI-; n = 141) group. All patients underwent left ventricular ejection fraction (LVEF, Echo) examination during the following 12 months. RESULTS: LVEF progressively decreased in the TnI+ group but not in the TnI- group. In TnI+ patients a close relationship between the TnI increase, as well as the number of positive TnI assays, and the maximal LVEF decrement, was found (r = -0.92, P < 0.0001 and r = -0.93, P < 0.0001, respectively). CONCLUSIONS: In our population, the elevation of TnI soon after HDC accurately predicts the development of future LVEF depression. In this setting, TnI can be considered a sensitive and reliable marker of myocardial damage with relevant clinical and prognostic implications.