The specific inhibition of the cardiac electrogenic sodium/bicarbonate cotransporter leads to cardiac hypertrophy.

Two alkalinizing mechanisms coexist in cardiac myocytes to maintain intracellular pH: sodium/bicarbonate cotransporter (electroneutral isoform NBCn1 and electrogenic isoform NBCe1) and sodium/proton exchanger (NHE1). Dysfunction of these transporters has previously been reported to be responsible for the development of cardiovascular diseases. The aim of this study was to evaluate the contribution of the downregulation of the NBCe1 to the development of cardiac hypertrophy. To specifically reduce NBCe1 expression, we cloned shRNA into a cardiotropic adeno-associated vector (AAV9-shNBCe1). After 28 days of being injected with AAV9-shNBCe1, the expression and the activity of NBCe1 in the rat heart were reduced. Strikingly, downregulation of NBCe1 causes significant hypertrophic heart growth, lengthening of the action potential in isolated myocytes, an increase in the duration of the QT interval and an increase in the frequency of Ca2+ waves without any significant changes in Ca2+ transients. An increased compensatory expression of NBCn1 and NHE1 was also observed. We conclude that reduction of NBCe1 is sufficient to induce cardiac hypertrophy and modify the electrical features of the rat heart.

Facial Mask and Plexiglass Box: a critical overview on the current strategies to protect patients from COVID-19 infection.

The route of transmission of SARS-CoV-2 has been understood thanks to the knowledge of previously identified human coronaviruses. According to these studies, the transmission of the virus occurs mainly between humans at close range, through respiratory droplets produced during conversation or coughing, as well as through direct contact of the hands then placed on the mucous membranes or mouth. From the final analysis of studies carried out on protective systems, the validity of plexiglass as a material to be used for the construction of protective devices could be affirmed. The plexiglass, in fact, would seem able to isolate the diffusion of aerosol particles dispersed by infected subjects and in different environments.

[The RAAS and SARS-CoV-2: A riddle to solve]. / El SRAA y el SARS-CoV-2: el acertijo a resolver.

The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as to the association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform health professionals about the current state of knowledge. Because this is an ever-evolving topic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS.

The alteration of stress-related physiological parameters after probiotics administration in oral surgeons with different degrees of surgical experience.

PURPOSE: Stress is a multifactorial and complex pathway, gaining growing attention from the healthcare community. Surgeons are subjected to higher levels of stress, due to surgical procedures that are demanding and repetitive; unfortunately, high-stress levels may also cause side-effects, as surgical mistakes. This study aimed to evaluate the efficacy of specific probiotics strains formula on stress levels in oral and maxillofacial surgeons, to improve their quality of life. METHODS: We have investigated the hormonal (salivary Cortisol; sC), immune (salivary Immunoglobulin A; sIgA) and cardiovascular (Heart rate, HR, and systolic blood pressure, SBP) responses induced by stress conditions in 40 oral surgeons, randomly selected and allocated, according to their experience level, in three categories: senior, expert, and junior. RESULTS: The results described how the number of heartbeats/ minute and SBP are slightly raised in all surgeons at different timepoints. Such data allow us to assess that work-related stress can induce an increase in cardiovascular parameters, even if they are not significantly modified by the use of probiotics. On the other hand, our data indicate that 10 weeks of probiotic integration may induce the improvement of other stress-related physiological parameters in oral surgeons with different degrees of surgical experience, such as the salivary cortisol levels, even under stress conditions. Moreover, in the test group (probiotics administration), the immunoglobulin levels were higher than the control (placebo administration) group: this happens as a consequence of the regular use of probiotics, which may induce an increased number of IgA producing cells. DISCUSSION: Our data indicated that 10 weeks of probiotics-enriched diet modify some stress-related physiological parameters in oral surgeons with different degrees of surgical experience, but it does not impact on the overall cardiovascular risk.

Gait changes following direct versus contralateral strength training: A randomized controlled pilot study in individuals with multiple sclerosis.

BACKGROUND: Contralateral strength training (CST) is increasingly investigated and employed as a non-conventional way to induce an indirect gain in strength in the weakened untrained limb. However, its effects on gait performance are more controversial. RESEARCH QUESTION: To assess and compare the effects of contralateral (CST) and direct (DST) strength training on spatio-temporal parameters, kinematic and kinetic descriptors of gait in persons with relapsing-remitting multiple sclerosis (PwMS). METHODS: Twenty-eight PwMS (EDSS 2.0-5.5) with inter-side difference in ankle dorsiflexors' strength ≥ 20 % and moderate gait impairment (walking speed 0.70-0.94 m/s), were randomly assigned to a CST (undergoing training of the less-affected dorsiflexors) or DST group (where the most-affected dorsiflexors were trained). Before and after a 6-week high-intensity resistance training (three 25-minute sessions/week), PwMS underwent bilateral measurements of dorsiflexors' maximal strength and assessment of gait spatio-temporal parameters, lower limb joint kinematics and kinetics. RESULTS AND SIGNIFICANCE: Following the training period, muscle strength increased significantly in both groups (on average, CST + 29.5 %, p < 0.0005; DST + 15.7 %, p = 0.001) with no difference between the two interventions. Significant changes in gait speed (+16.5 %; p < 0.0001) and stride length (+6.0 %; p = 0.04) were detected only after DST, while no difference was detected in the CST group. Ankle moment and ROM were unaffected by the training. In PwMS with mild to moderate disability and lower limb dorsiflexors' strength asymmetry, CST was not inferior to DST in inducing significant strength gains in the untrained most-affected limb. However, only DST significantly improved gait performance and, specifically, walking speed. Even though CST did not worsen asymmetry, data suggest that contralateral approaches should not be recommended straightaway if the training goal is to improve outcomes other than strength and, specifically, walking speed.

Narrow subpubic arch angle is associated with higher risk of persistent occiput posterior position at delivery.

OBJECTIVE: To determine whether the subpubic arch angle (SPA) measured by three-dimensional ultrasound is associated with the fetal occiput position at delivery and the mode of delivery. METHODS: Nulliparous women with an uncomplicated singleton pregnancy at ≥ 37 weeks' gestation were recruited from two tertiary centers between September 2013 and August 2015. All women underwent a three-dimensional transperineal ultrasound examination and the SPA was measured using the previously validated Oblique View Extended Imaging software. Data on the outcome of labor were obtained prospectively in all cases and the correlations between SPA and the fetal occiput position at delivery and the incidence of operative delivery were investigated. RESULTS: Overall, 368 women were included in the study. Fetal position at delivery was occiput anterior in 339 (92.1%) cases and occiput posterior (OP) in 29 (7.9%) cases. A significantly narrower SPA was found in the OP group compared with the occiput anterior group (104.4 ± 16.8° vs 116.4 ± 11.9°; P < 0.0001). The SPA was significantly narrower in women requiring obstetric intervention compared with in women with a spontaneous vaginal delivery. From multivariable logistic regression analysis, SPA and maternal height appeared to be significant predictors of both the fetal occiput position at delivery and the risk of operative delivery. The best cut-off value of SPA for predicting an OP position at delivery was 90.5°. CONCLUSION: A narrow SPA is associated with a higher risk of persistent OP position at delivery and of operative delivery. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Placental volume and uterine artery Doppler evaluation at 11 + 0 to 13 + 6 weeks' gestation in pregnancies conceived with in-vitro fertilization: comparison between autologous and donor oocyte recipients.

OBJECTIVE: To compare first-trimester uterine artery pulsatility index (UtA-PI) and three-dimensional (3D) placental volume in pregnancies conceived through in-vitro fertilization (IVF) using autologous or donor oocytes and pregnancies conceived naturally, and to relate these measurements to the development of pre-eclampsia (PE). METHODS: UtA-PI and placental volume were measured at 11 + 0 to 13 + 6 weeks of gestation in 416 IVF pregnancies (307 with autologous and 109 with donor oocytes) and in 498 spontaneously conceived pregnancies. We recruited nulliparous women with singleton pregnancy. The measured mean UtA-PI and placental volume values were converted to multiples of the expected normal median (MoM), adjusted for gestational age. MoM values of IVF pregnancies were compared with MoM values of the naturally conceived pregnancies and related to PE development. RESULTS: Placental volume was significantly reduced in IVF pregnancies (K = 169.3; P < 0.0001) compared with natural pregnancies. No difference was found in UtA-PI MoM between the two groups. Among IVF pregnancies, significantly lower placental volumes were seen in those that received donor oocytes when compared with those with autologous oocytes (z = 3.89; P < 0.001). In IVF pregnancies that developed PE, lower values of placental volume were demonstrated with respect to normotensive pregnancies (donor: U = 6.8; P = 0.009; autologous: U = 5.1; P = 0.023), whereas no difference was found in UtA-PI. Multivariate logistic regression analysis demonstrated that placental volume (odds ratio (OR), 1.97 (95% CI, 1.33-2.27)) and donor oocytes in IVF pregnancy (OR, 2.24 (95% CI, 1.5-2.83)) were independent predictors of PE, whereas autologous oocytes in IVF pregnancy were not found to be significant in the model. CONCLUSIONS: First-trimester placental volume, as assessed by 3D ultrasound, is reduced in IVF pregnancies and this reduction is more marked in those involving donor oocyte recipients. The relative decrease in placental volume in IVF pregnancies that developed PE suggests an etiological mechanism different from uterine perfusion in such patients. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Uterine artery Doppler evaluation in twin pregnancies at 11 + 0 to 13 + 6 weeks of gestation.

OBJECTIVES: To compare uterine artery pulsatility index (PI) obtained at 11 + 0 to 13 + 6 weeks of gestation in singleton and twin pregnancies and to evaluate changes in PI values of twin pregnancies developing pre-eclampsia (PE) or small-for-gestational age (SGA) of either one or both fetuses. METHODS: Uterine artery PI was measured in 421 twin pregnancies (384 dichorionic and 37 monochorionic) and in 500 singleton pregnancies. The measured mean and lowest uterine artery PI values were converted to multiples of the expected normal median (MoM) after correction for maternal body mass index, ethnicity and gestational age. The median PI-MoM values of twins were compared with those of singleton pregnancies. In twin pregnancies, PI-MoM values were analyzed according to chorionicity, development of early-onset (< 34 weeks) or late-onset (≥ 34 weeks) PE and SGA of one or both twins. RESULTS: Uterine artery PI-MoM was significantly lower in twin compared with singleton pregnancies (mean K = 174.31, P < 0.0001, lowest K = 139.27, P < 0.0001). However, there were no significant differences in the uterine artery PI-MoM values between monochorionic and dichorionic twins. The uterine artery PI in twin pregnancies that developed early-onset PE (P < 0.001) and SGA of both twins (P < 0.05) was higher than the uterine artery PI in uncomplicated twin pregnancies, whereas no differences were found for late PE or SGA of one twin. CONCLUSIONS: First-trimester placental impedance to flow, as assessed by uterine artery Doppler examination, is reduced in twin pregnancies, with no differences related to chorionicity. The relative increase of uterine artery PI found in twin pregnancies that developed early PE and SGA of both twins suggests that first-trimester uterine artery assessment may be useful in identifying such complications.

Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS).

Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.

Carbapenem non-susceptible Klebsiella pneumoniae from Micronet network hospitals, Italy, 2009 to 2012.

Carbapenem-resistant Klebsiella pneumoniae has recently been reported as a new, multidrug-resistant nosocomial pathogen in several hospitals from various Italian regions. Through Micronet, a new Italian sentinel laboratory-based surveillance network, we studied the trend of non-susceptibility of K. pneumoniae to selected carbapenems (imipenem and/or meropenem) in 14 of the 15 hospitals participating in the network. Analysis of data from 1 January 2009 to 30 April 2012 revealed a statistically significant increasing trend (p<0.01) in the proportion of carbapenem non-susceptible K. pneumoniae isolates from clinical specimens (from 2.2 % in 2009 to 19.4% in 2012). The increase in the proportion of non-susceptibility was very large for isolates from the respiratory tract (from 5.3% in 2009 to 38.5% in 2012) and blood (from 5.4% in 2009 to 29.2% in 2012). The results demonstrate the urgent need in Italy for infection control, guidelines, antibiotic stewardship programmes and utilisation of surveillance systems, such as Micronet, which are capable of receiving data from hospitals in real time for many pathogens and types of clinical specimens.

The role of three-dimensional ultrasound in the diagnosis of fetal congenital anomalies: a review.

The objective of this review was to establish whether three-dimensional (3D) and four dimensional (4D) ultrasonography adds diagnostic information to what is currently provided by two-dimensional (2D) ultrasound in the diagnosis of the most frequent fetal structural defects: congenital heart disease and central nervous system congenital anomalies. There are evidences suggesting that 3D ultrasound allows to reduce the operator dependency in the visualization of standard diagnostic planes, thus reducing the examination time require for the obstetric ultrasound examination, with minimal impact on the visualization quality of the anatomic landmarks. Furthermore, operators with minimal experience may record cardiac or brain volumes that can be successfully analyzed off-line locally or sent by internet to experts for remote review. As a consequence 3D ultrasonography promises to become the method of choice for diagnosis congenital structural defects.

An algorithm based on OmniView technology to reconstruct sagittal and coronal planes of the fetal brain from volume datasets acquired by three-dimensional ultrasound.

OBJECTIVE: To describe a novel algorithm, based on the new display technology 'OmniView', developed to visualize diagnostic sagittal and coronal planes of the fetal brain from volumes obtained by three-dimensional (3D) ultrasonography. METHODS: We developed an algorithm to image standard neurosonographic planes by drawing dissecting lines through the axial transventricular view of 3D volume datasets acquired transabdominally. The algorithm was tested on 106 normal fetuses at 18-24 weeks of gestation and the visualization rates of brain diagnostic planes were evaluated by two independent reviewers. The algorithm was also applied to nine cases with proven brain defects. RESULTS: The two reviewers, using the algorithm on normal fetuses, found satisfactory images with visualization rates ranging between 71.7% and 96.2% for sagittal planes and between 76.4% and 90.6% for coronal planes. The agreement rate between the two reviewers, as expressed by Cohen's kappa coefficient, was > 0.93 for sagittal planes and > 0.89 for coronal planes. All nine abnormal volumes were identified by a single observer from among a series including normal brains, and eight of these nine cases were diagnosed correctly. CONCLUSIONS: This novel algorithm can be used to visualize standard sagittal and coronal planes in the fetal brain. This approach may simplify the examination of the fetal brain and reduce dependency of success on operator skill.

Sagittal plane kinematic analysis of the six-minute walk test: a classification of hemiplegic gait.

AIM: The aim of this study was to propose a kinematic classification of gait according to six minute walk test performance. METHODS: Thirty-four hemiplegic subjects were enrolled. Six-minute walk test (SMWT), gait analysis and Walking Handicap Scale score (WHS) were measured. A k-means cluster analysis was used to classify the sample into three sub-groups which were homogeneous in spatio-temporal parameters, kinematic variables, and which reflected three meaningful levels of walking competency. RESULTS: Three clusters were identified: low-functioning walkers (Cluster 1) walked for 88-172 m; intermediate-functioning walkers (Cluster 2) walked for 180-302 m and high-functioning walkers (Cluster 3) were able to cover 349-430 m. The authors found homogeneous gait profiles in these subgroups. Between-group differences on kinematic data and WHS scores were also underlined. CONCLUSIONS: Cluster analysis was able to identify consistent gait characteristics of spatio-temporal, walking endurance and sagittal plane kinematic profiles in hemiplegic subjects and is useful for categorizing the levels of walking competency in these subjects.

The positive inotropic effect of endothelin-1 is mediated by mitochondrial reactive oxygen species.

We have previously demonstrated the participation of reactive oxygen species (ROS) in the positive inotropic effect of a physiological concentration of Angiotensin II (Ang II, 1 nM). The objective of the present work was to evaluate the role and source of ROS generation in the positive inotropic effect produced by an equipotent concentration of endothelin-1 (ET-1, 0.4 nM). Isolated cat ventricular myocytes were used to measure sarcomere shortening with a video-camera, superoxide anion (()O(2)(-)) with chemiluminescence, and ROS production and intracellular pH (pH(i)) with epifluorescence. The ET-1-induced positive inotropic effect (40.4+/-3.1%, n=10, p<0.05) was associated to an increase in ROS production (105+/-29 fluorescence units above control, n=6, p<0.05). ET-1 also induced an increase in ()O(2)(-) production that was inhibited by the NADPH oxidase blocker, apocynin, and by the blockers of mitochondrial ATP-sensitive K(+) channels (mK(ATP)), glibenclamide and 5 hydroxydecanoic acid. The ET-1-induced positive inotropic effect was inhibited by apocynin (0.3 mM; 6.3+/-6.6%, n=13), glibenclamide (50 microM; 8.8+/-3.5%, n=6), 5 hydroxydecanoic acid (500 microM; 14.1+/-8.1, n=9), and by scavenging ROS with MPG (2 mM; 0.92+/-5.6%, n=8). ET-1 enhanced proton efflux (J(H)) carried by the Na(+)/H(+) exchanger (NHE) after an acid load, effect that was blocked by MPG. Consistently, the ET-induced positive inotropic effect was also inhibited by the NHE selective blocker HOE642 (5 microM; 9.37+/-6.07%, n=7). The data show that the effect of a concentration of ET-1 that induces an increase in contractility of about 40% is totally mediated by an intracellular pathway triggered by mitochondrial ROS formation and stimulation of the NHE.

Cost-effectiveness of new targeted therapy sunitinib malate as second line treatment in metastatic renal cell carcinoma in Argentina

Objetivo: el objetivo del estudio fue estimar el costo-efectividad del malato de sunitinib versus el mejor cuidado paliativo (best supportive care BSC) en el tratamiento de carcinoma de células renales metastásico resistente a citoquinas (mRCC) en pacientes que fallaron a interleuquina 2 (IL-2), interferón alfa o una combinación de ambos. Métodos: se desarrollo un modelo de Markov y se adaptó a las circunstancias argentinas. Los resultados de efectividad fueron tomados de estudios clínicos y de la base de datos de US Medicare. Los datos fueron ajustados con las estimaciones de mortalidad general de la población tomadas de fuentes argentinas. Las utilidades fueron colectadas con la ayuda del cuestionario EQ-5D en el estudio clínico. La principal fuente de datos de uso de recursos y costos fueron tomados de un instituto oncológico de Argentina. Los costos fueron calculados en pesos argentinos (AR$) de 2006. Tanto los costos como la efectividad fueron descontados a una tasa anual de 3%. El costo-efectividad incremental fue calculado por mes libre de progresión (PFM), año de vida ganado (YLG) y año de vida ajustado por calidad (QALY). Se efectuó un análisis de sensibilidad determinístico y probabilístico para las variables de efectividad y costo.

Introduction: The objective of this study was to estimate the cost-effectiveness of sunitinib malate versus the best palliative care (BSC best supportive care) in the treatment of metastatic renal cell carcinoma resistant to cytokines (MRCC) in patients who failed to interleukin 2 ( IL-2), interferon alpha or a combination of both. Methods: We developed a Markov model and was adapted to the circumstances in Argentina. The results of effectiveness were obtained from clinical studies and the database of U.S. Medicare. The data were adjusted by the estimates of mortality of the population taken from Argentine sources. The utilities were collected with the help of the EQ-5D questionnaire in the clinical study. The main source of data for resource use and costs were taken from an oncology institute in Argentina. The costs were calculated in Argentine pesos (AR $), 2006. Both the costs and effectiveness were discounted at an annual rate of 3%. The cost-effectiveness was estimated by progression-free months (PFM), year of life gained (YLG) and years of life adjusted for quality (QALY). An analysis of deterministic and probabilistic sensitivity for the variables of cost and effectiveness.

Visual EMG Biofeedback to Improve Ankle Function in Hemiparetic Gait.

Spasticity in stroke patients interferes with coordinated muscle firing patterns of the lower extremity leading to gait abnormalities. The goal of this study was to improve ankle function during walking by augmenting treadmill gait retraining with a visual EMG biofeedback technique. Eight stroke patients who could ambulate between 0.5 and 0.9 m/s participated in the study. The training consisted of 12 sessions of treadmill walking during which the activity of the tibialis anterior and gastrocnemius lateralis muscles of the affected side was displayed on a computer screen. Targets were shown to indicate to the subject when to activate the monitored muscles. Gait evaluations were performed before and after the training period to test the hypothesis that ankle mechanics improved following the intervention. Improvements in gait function were characterized by changes in temporal gait parameters and lower extremity kinematics and kinetics. Subjects showed an increase in gait speed, time of single leg support on the affected side, ankle power generation at push-off and a reduction in knee extensor moment. These results indicate that treadmill gait retraining augmented via visual EMG-biofeedback facilitates improvements in hemiparetic gait.

Positive inotropic and negative lusitropic effect of angiotensin II: intracellular mechanisms and second messengers.

In the cat ventricle angiotensin II exerts a positive inotropic effect produced by an increase in intracellular calcium associated with a prolongation of relaxation. The signaling cascades involved in these effects as well as the subcellular mechanisms of the negative lusitropic effect are still not clearly defined. The present study was directed to investigate these issues in cat papillary muscles and isolated myocytes. The functional suppression of the sarcoplasmic reticulum (SR) with either 0.5 microm ryanodine or 0.5 microm ryanodine plus 1 microm thapsigargin or the preincubation of the myocytes with the specific inhibitor of the inositol 1,4,5-triphosphate (IP3) receptors [diphenylborinic acid, ethanolamine ester (2-APB), 5-50 microm] did not prevent the positive inotropic effect and the increment in Ca2+ transient produced by 1 microm angiotensin II. In contrast, protein kinase C (PKC) inhibitors, chelerythrine (20 microm) and calphostin C (1 microm) completely inhibited both, the angiotensin II-induced increase in L-type calcium current and positive inotropic effect. The prolongation of half relaxation time produced by 0.5 microm angiotensin II [207+/-15.4 msec (control) to 235+/-19.98 msec (angiotensin II), P<0.05] was completely blunted by PKC inhibition. This antirelaxant effect, which was independent of intracellular pH changes, was associated with a prolongation of the action potential duration and was preserved after either the inhibition of the SR and the SR Ca2+ ATPase (ryanodine plus thapsigargin) or of the reverse mode of the Na+/Ca2+ exchanger (KB-R7943, 5 microm). We conclude that in feline myocardium the positive inotropic and negative lusitropic effects of angiotensin II are both entirely mediated by PKC without any significant participation of the IP3 limb of the phosphatidylinositol/phospholipase C cascade. The results suggest that the antirelaxant effect of angiotensin II might be determined by the decrease in Ca2+ efflux through the Na+/Ca2+ exchanger produced by the angiotensin II-induced prolongation of the action potential duration.

Immunotherapy of metastatic kidney cancer.

From April 1986 to September 2000, 122 MRCC patients were treated by monthly intralymphatic injections (containing a mean of 573 IL-2 U and 26 x 10(6) LAK cells) and i.m. administration of IFN and TF; 71 patients also received a 3-day cycle of monthly IL-2 inhalations with a mean of 998 daily U. MRCC cases not treated by immunotherapy (n = 89) represent our historical controls. Adverse clinical side effects related to treatment were negligible. CR (n = 11) and PR (n = 13) were noticed in 24/122 patients. Of 24 responding patients, 17 resumed progression, whereas 7 remain in remission 11-69 months later. The overall median survival of treated patients (28 months) was 3.5-fold higher than the median survival of historical controls (7.5 months), and a Kaplan-Meier curve showed 25% survival 11 years after the beginning of immunotherapy. Apparently, the addition of IL-2 by inhalation improved survival. The present immunotherapy protocol appears to be efficacious, safe, devoid of adverse side effects, far less costly than others and able to offer a good quality of life to MRCC patients; if confirmed in a multicenter trial, it could set the basis for developing low-dose immunomodulatory treatments.