Alessandro Martinoni

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.

Minor Increases in Plasma Troponin I Predict Decreased Left Ventricular Ejection Fraction after High-Dose Chemotherapy

BACKGROUND Increased cardiac troponin I (cTnI) in patients treated with high-dose chemotherapy (HDCT) for aggressive malignancy has been proposed as an early marker of late HDCT-induced cardiac dysfunction. We investigated whether cTnI measured by the Stratus CS (Dade Behring) would allow detection of minimal cTnI increases in patients treated with HDCT. METHODS Plasma cTnI concentrations were determined in 179 consecutive patients before HDCT, at the end of the treatment, and after 12, 24, 36, and 72 h. Cardiac function was explored by echocardiography, and left ventricular ejection fraction (LVEF) was recorded during follow-up. The greatest variation in LVEF from the baseline value was used as a measure of cardiac damage. RESULTS In 99 healthy volunteers, the 99th percentile was at 0.07 microg/L. On the basis of ROC curve analysis (area under the curve, 0.89), a cutoff of 0.08 microg/L was chosen (sensitivity, 82%; specificity, 77%). cTnI > or =0.08 microg/L occurred in 57 patients (32%) with echocardiographic monitoring revealing a mean decrease in LVEF of 18%. In comparison, the group of cTnI-negative patients had a mean decrease in LVEF of 2.5% (P <0.001). CONCLUSIONS Plasma cTnI, as measured with the Stratus CS, can detect minor myocardial injury in patients treated with HDCT.

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.

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.ZusammenfassungPerikarderguss und Herzbeuteltamponade finden sich nicht selten als Folge fortgeschrittener maligner Erkrankungen, wie zum Beispiel bei Bronchial- und Mammakarzinomen sowie bei Lymphomen und Leukämien. Eine vorübergehende Entlastund kann durch die perkutane ultraschall- oder durchleuchtungskontrollierte Perikardpunktion erreicht werden. Dieses Vorgehen wird auch von schwer kranken Patienten gut toleriert und ist mit keiner nennenswerten Morbidität oder Mortalität verbunden. Allerdings werden Rezidive in bis zu 40% der Fälle beobachtet.Deshalb wurden bislang drei wesentliche alternative Vorgehensweisen entwickelt: 1. eine Perikardpunktion mit intraperikardialer Sklerotherapie, 2. eine perkutane Ballonperikardiotomie und 3. die operative Perikardfensterung entweder als subxyphoidale oder transthorakale Perikardiotomie oder als thorakoskopische Perikardfensterung. Zwar wird das chirurgische Vorgehen in der chirurgischen Literatur favorisiert, dagegen empfehlen kardiologische Zentren vor allem bei kritisch kranken Patienten ein kardiologisches Vorgehen mit Perikardpunktion und Sklerotherapie. Offensichtlich ist eine intraperikardiale Skerotherapie wesentlich schonender als das chirurgische Vorgehen. Außerdem wird hierdurch auch die Verschleppung von Tumorzellen in Pleura und Peritoneum vermieden.Unter intraperikardialer Sklerotherapie versteht man die Instillation von Substanzen, die sklerosierende und zytostatische Aktivität besitzen, wie zum Beispiel Tetracycline, Bleomycin, Thiotepa, Cisplatin oder Radionuklide.Tetracycline: Maher et al. konnten in einer größeren retrospektiven Studie zeigen, dass von 85 mittels Sklerotherapie behandelten Patienten 79% in den ersten 30 Tagen ohne Rezidiv blieben. Die Therapie mit Tetracyclinen ist allerdings mit einer hohen Nebenwirkungsrate verbunden: Fieber und Vorhofarrhythmien werden in 10%, retrosternale Schmerzen in 20% der Fälle beobachtet. Deshalb wird zur pH-Neutralisierung die Beimengung von Blut in das intraperikardiale Instillat empfohlen.Bleomycin: Liu et al. untersuchten 29 Patienten retrospektiv, die mit Bleomycin oder Doxycyclin behandelt wurden. Die Wirksamkeit beider Substanzen war ähnlich, Bleomycin wurde aber besser toleriert. Größere prospektive Studien fehlen.Thiotepa (Triethylenphosphoramid): Thiotepa ist eine alkylierende Substanz, die über lange Zeit in der Therapie von soliden Tumoren und Pleuraergüssen eingesetzt wurde, da sie sowohl sklerosierende als auch zytostatische Eigenschaften besitzt. Girardi et al. und Colleoni et al. behandelten insgesamt 60 Patienten mit verschiedenen Therapieregimen. Wesentliche Komplikationen oder Nebenwirkungen wurden nicht berichtet. Die Rezidivrate 30 Tage nach der Behandlung betrug 83%.Cisplatin: Zahlreiche Studien zeigen einen Therapieerfolg bei malignen intraperitonealen Ergüssen. Mehrere Studien wurden auch zur Behandlung von Perikardergüssen publiziert. Die Wirksamkeit mit rezidivfreien Intervallen von zwei bis 24 Monaten (Median zwei bis drei Monate) ist gut, die Nebenwirkungsrate sehr niedrig.Andere Medikamente: Weitere Therapievorschläge umfassen die Immunmodulatoren (IFN, Il-2, OK 432) oder anderen zytostatischen Substanzen (5-FU oder Aclarubicine).Radiotherapie: Insbesondere für die Therapie radiosensitiver Tumoren wurde eine externe Radiotherapie vorgeschlagen. Auch die intraperikardiale Applikation von 32P-Kolloid ist mit sehr guten Ansprechraten (komplette Remission in 95% im Mittel für acht Monate) ohne signifikante Nebenwirkungen vergesellschaftet.Aufgrund der Datenlage kann eine allgemeine Empfehlung zur Therapie maligner Perikardergüsse gegenwärtig noch nicht gegeben werden. Dazu fehlen randomisierte, kontrollierte Multicenterstudien mit ausreichend großen Fallzahlen. Unserer Auffassung nach ist aber die Perikardpunktion in Kombination mit einer intraperikardialen Sklerotherapie, zum Beispiel mit Thiotepa oder Cisplatin, den chirurgischen Verfahren vorzuziehen, da Rezidiv- und Komplikationsraten sowie die Kosten gering sind.

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-Hodgkins lymphoma, Hodgkins disease, relapsed ovarian cancer, Ewings 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.

Impact of limited pulmonary function on the management of resectable lung cancer.

AIMS Limited pulmonary function (LPF) related to obstructive disease and emphysema or due to significant lung toxicity resulting from chemotherapy regimens are frequent co-morbidity factors in lung cancer patients. Purpose of this study was to investigate the frequency of LPF in lung cancer and its impact of on surgical eligibility and postoperative outcome. MATERIALS AND METHODS We analyzed a series of 255 consecutive patients with otherwise resectable lung cancer, admitted to our department between January 1998 and December 1999. Patients were considered affected by LPF if their forced expiratory volume in one second (FEV1%) and/or diffusing lung capacity for carbon monoxide (DLCO%) was less than 50% of predicted normal values. Perioperative mortality, major and minor complications were analysed according to lung function status. RESULTS A total of 42 (16.5%) patients presented with significant limitations of the pulmonary function (LPF). Of these, 11 (26%) cases were excluded from surgery because of the severity of pulmonary disease. In the group of 244 patients who underwent surgery, the 31 LPF cases showed a slightly higher frequency of preoperative induction therapies (42 vs. 30%) and sublobar resections (33 vs. 8%) in comparison with the other 213 resected cases. However, no difference was observed in median hospital stay (7 days in both groups), major morbidity (13 vs. 11%) or mortality (0 vs. 1.4%). CONCLUSIONS A strict and careful selection of patients, guided by concurrent analysis of different functional tests, allowed to offer surgery with a very low complication rate to the majority of patients with limited pulmonary function. A volume reduction effect was evident in selected patients with severe emphysema.

LombardIMA: A regional registry for coronary angioplasty in ST-elevation myocardial infarction

Background Percutaneous coronary intervention (PCI) has been shown to be the best reperfusion therapy for acute myocardial infarction with ST-elevation (STEMI), but data from registries show differences in patient populations and outcomes between randomized trials and real life. Objectives We sought to provide information about the current status of this treatment with a registry collecting data in Lombardy, the most densely populated region in Italy, with widespread availability of cathlabs and a well-established network for the treatment of STEMI. Methods and results Patient enrolment was performed by 32 hub centres recruiting 3901 STEMI patients who underwent PCI procedures within 12 h of the onset of symptoms, of whom 3317 patients underwent primary PCI, 376 ‘facilitated’ PCI, and 208 rescue PCI in cathlabs located, in 77% of cases, in the same hospital of admission. In-hospital and 30-day total death were 4.4 and 6.6%, respectively. At multivariate analysis independent negative predictors of 30-day mortality were Killip class 3–4, number of involved ECG leads, chronic renal failure and age, whereas positive predictors were ST resolution more than 50% and postprocedural grade 3 thrombolysis in myocardial infarction flow. Conclusions LombardIMA PCI registry enrolled STEMI patients representing a real-world population treated with PCI. Findings presented in this study may provide a benchmark for similar registries undertaken in other Italian regions and may be helpful to assess future possible developments of care for STEMI patients.

Defining high-risk patients with ST-segment elevation acute myocardial infarction undergoing primary percutaneous coronary intervention: a comparison among different scoring systems and clinical definitions.

BACKGROUND Identification of high-risk patients with ST-segment elevation acute myocardial infarction (STEMI) is of the utmost importance for adequate patient stratification and evaluation of additive treatments. However, there is no consensus on the optimal definition of high-risk patients. METHODS We therefore compared 5 scoring systems in the assessment of the risk of 30-day mortality in 3214 patients with STEMI treated with primary percutaneous coronary intervention (PCI). RESULTS Clinical scores showed a large variability in risk stratifying patients. Identification of high-risk patients ranged from 15% (PAMI score ≥ 9) to 66% (McNamara definition). McNamara, Antoniucci and Brodie definitions had the best sensitivity (0.87-0.88 and 95% confidence intervals (CI) ranging from 0.82-0.93) while PAMI ≥ 9 had the best specificity (0.87 with 95% CI of 0.86-0.88), while its sensitivity was quite low (0.42). In a sample size simulation of a trial aimed at demonstrating a 33% difference in 30-day mortality between two hypothetical treatments, the number of STEMI patients needed to be screened varied from 4712 for the Brodie definition to 9038 for the PAMI ≥ 9 score. CONCLUSIONS There is a large variability in risk stratification, sensitivity, specificity and predictive values among different scoring systems. These considerations should be taken into account when designing randomised trials.