Balancing cancer immunotherapy and immune-related adverse events: The emerging role of regulatory T cells.

Advances in our understanding οf tumor immunity have prompted a paradigm shift in oncology, with the emergence of immunotherapy, where therapeutic agents are used to target immune cells rather than cancer cells. A real breakthrough in the field of immunotherapy came with the use of immune checkpoint inhibitors (ICI), namely antagonistic antibodies that block key immune regulatory molecules (checkpoint molecules), such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1, that under physiologic conditions suppress T cell effector function. However, despite the enormous success, a significant proportion of patients do not respond, while responses are frequently accompanied by life-threatening autoimmune related adverse events (irAEs). A major impediment in the effectiveness of ICI immunotherapy is the tumoral resistance, which is dependent on the immunosuppressive nature of tumor microenvironment (TME). Regulatory T cells (Tregs) are among the most abundant suppressive cells in the TME and their presence has been correlated with tumor progression, invasiveness as well as metastasis. Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function. Notably, Tregs amply express most of the checkpoint molecules such as CTLA4, PD1 and LAG3 and therefore represent a direct target of ICI immunotherapy. Taking into consideration the critical role of Tregs in maintenance of immune homeostasis and avoidance of autoimmunity it is plausible that targeting of Tregs by ICI immunotherapy results in the development of irAEs. Since the use of ICI becomes common, and new immune checkpoint molecules are currently under clinical trials for the treatment of cancer, the occurrence of irAEs is expected to dramatically rise. Herein we review the current literature focusing on the role of Tregs in cancer evolution, ICI response and development of irAEs. Unraveling the complex mechanisms that hinder the tumor immune surveillance and in particular how ICI immunotherapy imprint on Treg activities to promote cancer regression while avoid development of irAEs, will empower the design of novel immunotherapeutic modalities in cancer with increased efficacy and diminished adverse events.

Usefulness of echocardiography in the prognostic evaluation of non-Q-wave myocardial infarction.

Patients with non-Q-wave myocardial infarction (MI) are a heterogeneous population with a wide range of coronary disease severity and extent of myocardial necrosis, showing, therefore, different electrocardiographic findings and different outcomes. To evaluate the role of echocardiography in the management of non-Q-wave MI patients, 192 consecutive patients without previous MI were studied (78 with ST segment elevation, 56 with ST depression and 58 without ST modifications). All patients underwent 2-dimensional echocardiography (16-segment model) within 24 hours of admission to the coronary care unit. Wall-motion abnormalities, wall-motion score index, ejection fraction, and end-diastolic and end-systolic volumes were evaluated. In 35 patients, death, reinfarction, recurrent angina, or severe heart failure occurred during the in-hospital phase, whereas the remaining 157 patients had a good outcome. Patients with a poor prognosis were older (68 +/- 6 vs 59 +/- 5 years, p < 0.01), had a worse left-ventricular function (wall-motion score index 1.4 +/- 0.4 vs 1.25 +/- 0.3, p < 0.05; end-systolic volume 54 +/- 25 vs 38 +/- 12 mL/m2, p < 0.01; ejection fraction 50 +/- 10 vs 58 +/- 8%, p < 0.01), and presented more frequently with ST segment depression (49 vs 25%, p < 0.01). The positive and negative predictive values for early clinical events were, respectively: ST segment depression 0.30 and 0.87; wall-motion abnormalities in > 3 segments 0.28 and 0.86; wall-motion score index > 1.33 = 0.28 and 0.87; end-diastolic volume > 46 mL/m2 = 0.49 and 0.91; ST segment depression and wall-motion abnormalities in > 3 segments 0.60 and 0.88. These results underline the usefulness of echocardiography in the early risk stratification of non-Q-wave MI patients, together with electrocardiographic data. Patients with ST segment depression and more extensive wall-motion abnormalities are at higher risk and their management needs a more aggressive approach.

Chlamydia pneumoniae infection and atherosclerotic coronary disease.

BACKGROUND: Previous works have suggested an association between Chlamydia pneumoniae infection and coronary heart disease. We evaluated the prevalence of C. pneumoniae infection in patients with acute myocardial infarction (AMI) and coronary heart disease (CHD). METHODS AND RESULTS: Ninety-eight patients with AMI, 80 patients with CHD, and 50 control subjects matched for age and sex were investigated. Immunoglobulin (Ig)M, IgG, and IgA antibodies to C pneumoniae were measured by the microimmunofluorescence test. IgM antibodies were not found; IgG positivity was found in 58.2% of the AMI group, 60.0% of the CHD group, and 38% of the control group, whereas for IgA, positivity was found in 33.7%, 43.7%, and 22% of cases in AMI, CHD, and control groups, respectively. Titers indicating reinfection were found in AMI and CHD groups in 6.1% and 10%, respectively, whereas titers indicating chronic infection were found in 14% of the AMI group and 25% of the CHD group. A significant correlation was found between chronic C pneumoniae infection and dyslipidemias in the AMI and CHD groups (P =.003; P =. 0006). CONCLUSIONS: The results suggest that chronic C pneumoniae infection may be associated with the development of atherosclerotic coronary disease. In our next step, we will test whether antichlamydial antibiotics may help to reduce the risk of atherosclerotic disease.

[Stress echocardiography in the study of the warm-up phenomenon]. / L'ecocardiografia da sforzo nello studio del fenomeno del warm-up.

To date, the "warm-up" phenomenon in patients has been evaluated by ECG and symptom analysis. We investigated the warm-up phenomenon with supine bicycle stress echocardiography in patients with coronary artery disease documented by angiography and positive stress echocardiography. Sixteen coronary artery disease patients (54 +/- 9 years), who were off treatment throughout the study, were enrolled. Each of them underwent two consecutive exercise tests (25 W/2 min) with a 10-min recovery to reestablish baseline conditions. At the end of each stage of exercise and at peak exercise, when wall motion abnormalities (WMA), 1 mm ST depression and angina occurred, and at each minute, for the first 6 min of recovery, a 12-lead ECG was recorded and rate-pressure product was calculated. Time of onset and duration of 1 mm ST depression, WMA and angina, were also determined. Peak WMA, peak wall motion score index, duration of exercise and severity of angina were also evaluated. Exercise time duration and peak rate-pressure product were greater during the second than the first test (p = 0.02, p = 0.03 respectively); the second test also showed a longer delay of the onset of 1 mm ST depression and WMA (p = 0.01, p = 0.01 respectively) and higher rate--pressure product values (p = 0.04, p = 0.03 respectively). On the contrary, wall motion score index during the first and the second test was similar. Time to angina onset was longer during the second test (p = 0.03); the recovery period of ST depression and WMA was shorter during the second test (p = 0.02). In conclusion, these preliminary data show that patients tolerated the second period of ischemia better than the first, consistent with the presence of the warm-up phenomenon. However, the similarity of values of wall motion score index and WMA did not support a reduction in the ischemic area during the second test. This is in contrast with a possible modification of myocardial metabolism which typically underlies the ischemic preconditioning.

Echocardiography in the coronary care unit: diagnostic and prognostic impact in comparison with clinical and other indicators.

The clinical arena in which we must consider the role of echocardiography is characterized by 2 fundamental findings: (1) most patients with chest pain and suspected acute myocardial infarction (MI) do not present diagnostic electrocardiograms; and (2) an early and correct diagnosis is necessary to match the patient with the most adequate treatment. Echocardiography may be very useful in the coronary care unit, allowing a correct diagnosis of ischemic heart disease when electrocardiography is unclear, even before the rise of cardiac enzymes is detected. It may also play a role in decision-making for thrombolytic therapy. In addition, echocardiography provides useful information for early risk stratification. In fact, although high-risk patients are well identified by simple clinical or instrumental variables (i.e., Killip classification, enzymatic data, blood-gas analysis, electrocardiogram, etc.), most patients (>60%) are identified as low risk, and several subjects classified into the low-risk groups have a poor prognosis and are not detected using a single variable. In our experience, 2-dimensional echocardiography was able to further stratify between patients of low-risk classes. Therefore, echocardiography plays an important role in the early stratification of acute MI patients, especially in those without signs or symptoms of heart failure.

[Chlamydia pneumoniae infection and cardiac ischemic syndromes]. / Infezione da Chlamydia pneumoniae e sindromi ischemiche cardiache.

The aim of this study was to assess the presence of Chlamydia pneumoniae antibodies in patients with angiographically verified atherosclerotic coronary artery disease. A total of 114 consecutive patients were investigated between April 1995 and June 1996. Patients were divided into two groups: 72 patients with acute myocardial infarction (AMI; 53 men, 19 women, mean age 62.27 +/- 10.1 years), and 42 patients with chronic ischemic heart disease (CAD; 37 men, 5 women, mean age 62.75 +/- 9.2 years). A control group of 50 normal subjects matched for age (mean 62 +/- 9 years), sex, social status and geographical area was used. Identification of Chlamydia pneumoniae was carried out with the microimmunofluorescence method, on two serum samples taken from patients on admission and after 15 days. The IgM, IgG and IgA anti-Chlamydia pneumoniae titers were assessed, values > or = 1:16, > or = 1:32 and > or = 1:8 being respectively considered positive. Acute (IgM > or = 16 or four fold rise of IgG titer) and chronic (IgG > or = 128 e IgA > or = 32 or only elevated IgA titer) infections were analyzed. IgM antibodies were not found in AMI, CAD and control groups. IgG positivity (IgG > or = 32) was found in 38% of the control group, in 58.3% of the AMI group (p < 0.05) and 42.8% of the CAD group (p < 0.01). IgA positivity > or = 8) was found in 22% of the control group, in 31.9% of the AMI group (NS) and in 33.3% of the CAD group (p < or = 0.05). Acute infection was observed in 5.5% of AMI patients and in 12% of CAD patients (NS), whereas no subject of the control group showed these values. Chronic infection was observed in 9.7% of AMI patients and in 16.6% of CAD patients (NS) whereas nobody of the control group showed these values. In conclusion, our results suggest that Chlamydia pneumoniae infection is present only in the AMI and CAD groups. It is possible to suppose that this infection may be linked to atherosclerosis through an endothelial damage or a systemic endogenous procoagulant and inflammatory activity.

[At risk myocardium after acute infarct treated with fibrinolysis: assessment using exertion echocardiography and clinico-prognostic significance]. / Miocardio a rischio dopo infarto acuto trattato con fibrinolisi: rilevamento mediante ecocardiografia da sforzo e significato clinico-prognostico.

Several studies have been carried out on the role of exercise echocardiography for risk stratification after uncomplicated myocardial infarction. However, the diffusion of thrombolysis has entailed a remarkable change in the characteristics of these patients, with a major incidence of recurrent ischemic events or reinfarction in the follow-up. To test whether the predictive value of exercise echocardiography may be modified by thrombolytic treatment, we have studied 62 patients with acute myocardial infarction undergoing lytic therapy (Group A), compared to 153 conventionally-treated patients (Group B). All patients were asymptomatic at the time of the test, performed by cycloergometer 14 days after hospital admission. In 125 patients (47 Group A and 78 Group B) predischarge coronary angiography was performed. The exercise test showed a lower, but not significant, rate of positive tests in Group A patients (51.6 vs 58.8%). However, a positive test was more frequent in the homozonal area among patients who underwent thrombolytic therapy (50% of positive tests vs 18% in Group B; p < 0.001). Follow-up data (23 +/- 17 months) showed a higher but not significant rate of coronary events (cardiac death, reinfarction, severe angina, coronary bypass or angioplasty) in Group A patients with a positive test (62 vs 39% in Group B); however, in the subgroup with homozonal positive test, the event rate was much higher in Group A (77 vs 18% in Group B; p < 0.01). Furthermore, among patients with negative exercise test, coronary events were observed in 8% Group A and in 10% Group B patients. Therefore, our results show a higher percentage of homozonal exercise-induced ischemia with subsequent higher rate of coronary events in the thrombolyzed patients with respect to controls. This pattern is probably due to a higher rate of significant infarct-related residual stenosis, as coronary angiography have demonstrated. In conclusion, exercise echocardiography is useful in thrombolyzed patients, since it may better explore, rather than ECG, peri-necrotic areas.

Genetic polymorphisms and intrauterine development. Evidence of decreased heterozygosity in light-for-dates human newborn babies.

In 2 independent samples of low-birth-weight infants the proportion of females and homozygotes for a series of polymorphic systems was higher in light-for-dates than in preterm babies. The observation seems to give support to the hypothesis that homozygosity for 'normal' polymorphisms may decrease in general intrauterine growth rate. Since it is known that survival rate is strongly related to birth weight, a correlation between growth retardation and homozygosity may have a major role in the maintenance of such polimorphisms.