Brain network dynamics in the alpha band during a complex postural control task.

Objective.To decipher brain network dynamic remodeling from electroencephalography (EEG) during a complex postural control (PC) task combining virtual reality and a moving platform.Approach.EEG (64 electrodes) data from 158 healthy subjects were acquired. The experiment is divided into several phases, and visual and motor stimulation is applied progressively. We combined advanced source-space EEG networks with clustering algorithms to decipher the brain networks states (BNSs) that occurred during the task.Main results.The results show that BNS distribution describes the different phases of the experiment with specific transitions between visual, motor, salience, and default mode networks coherently. We also showed that age is a key factor that affects the dynamic transition of BNSs in a healthy cohort.Significance.This study validates an innovative approach, based on a robust methodology and a consequent cohort, to quantify the brain networks dynamics in the BioVRSea paradigm. This work is an important step toward a quantitative evaluation of brain activities during PC and could lay the foundation for developing brain-based biomarkers of PC-related disorders.

The Italian Society of Andrology and Sexual Medicine (SIAMS), along with ten other Italian Scientific Societies, guidelines on the diagnosis and management of erectile dysfunction.

PURPOSE: Erectile dysfunction (ED) is one of the most prevalent male sexual dysfunctions. ED has been in the past mistakenly considered a purely psycho-sexological symptom by patients and doctors. However, an ever-growing body of evidence supporting the role of several organic factors in the pathophysiological mechanisms underlying ED has been recognized. METHODS: The Italian Society of Andrology and Sexual Medicine (SIAMS) commissioned an expert task force involving several other National Societies to provide an updated guideline on the diagnosis and management of ED. Derived recommendations were based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: Several evidence-based statements were released providing the necessary up-to-date guidance in the context of ED with organic and psychosexual comorbidities. Many of them were related to incorrect lifestyle habits suggesting how to associate pharmacotherapies and counseling, in a couple-centered approach. Having the oral therapy with phosphodiesterase type 5 inhibitors as the gold standard along with several other medical and surgical therapies, new therapeutic or controversial options were also discussed. CONCLUSIONS: These are the first guidelines based on a multidisciplinary approach that involves the most important Societies related to the field of sexual medicine. This fruitful discussion allowed for a general agreement on several recommendations and suggestions to be reached, which can support all stakeholders in improving couple sexual satisfaction and overall general health.

Postural control paradigm (BioVRSea): towards a neurophysiological signature.

Objective.To define a new neurophysiological signature from electroencephalography (EEG) during a complex postural control task using the BioVRSea paradigm, consisting of virtual reality (VR) and a moving platform, mimicking the behavior of a boat on the sea.Approach.EEG (64 electrodes) data from 190 healthy subjects were acquired. The experiment is composed of 6 segments (Baseline, PRE, 25%, 50%, 75%, POST). The baseline lasts 60 s while standing on the motionless platform with a mountain view in the VR goggles. PRE and POST last 40 s while standing on the motionless platform with a sea simulation. The 3 other tasks last 40 s each, with the platform moving to adapt to the waves, and the subject holding a bar to maintain its balance. The power spectral density (PSD) difference for each task minus baseline has been computed for every electrode, for five frequency bands (delta, theta, alpha, beta, and low-gamma). Statistical significance has been computed.Main results.All the bands were significant for the whole cohort, for each task regarding baseline. Delta band shows a prefrontal PSD increase, theta a fronto-parietal decrease, alpha a global scalp power decrease, beta an increase in the occipital and temporal scalps and a decrease in other areas, and low-gamma a significant but slight increase in the parietal, occipital and temporal scalp areas.Significance.This study develops a neurophysiological reference during a complex postural control task. In particular, we found a strong localized activity associated with certain frequency bands during certain phases of the experiment. This is the first step towards a neurophysiological signature that can be used to identify pathological conditions lacking quantitative diagnostics assessment.

Vagal nerve stimulation cycles alter EEG connectivity in drug-resistant epileptic patients: A study with graph theory metrics.

OBJECTIVE: Vagal Nerve Stimulation (VNS) is an effective treatment for Drug-Resistant (DR) epilepsy. Albeit the corroborated effectiveness of VNS, little is known about how VNS works. We aim to leverage quantitative Electroencephalography (qEEG) to study how the brain responds to VNS cycles. METHODS: Eighteen subjects with DR epilepsy were enrolled in our study. 64-channel EEG was recorded during VNS stimulation. Periods of stimulation (VNS), preceding (preVNS) and following stimulation (postVNS) were identified via an electrode placed on the stimulator. We used qEEG analysis to assess changes in spectral and network activity that characterize these conditions. Graph theory metrics were used to calculate differences in network connectivity. RESULTS: No differences were found in spectral activity between preVNS, VNS, and postVNS. Graph theory showed consistent changes in network organization expressed by Small World Index (SWI), Betweenness Centrality (BtwC), and Global Efficiency (gE). These changes were most significant in the slow EEG bands. CONCLUSIONS: In DR epilepsy, VNS has a significant effect on brain network activity, as assessed by EEG connectivity, acting on widespread network distribution rather than band-power. SIGNIFICANCE: Our findings support the hypothesis that VNS acts on epilepsy by influencing diffuse network connectivity in the brain.

Hypersexuality as a tip of the iceberg of a primary psychopathology: a joined position statement of the Italian Society of Andrology and Sexual Medicine (SIAMS) and of the Italian Society of Psychopathology (SOPSI).

In the last years, hypersexual behavior has been broadly scientifically studied. The interest in this topic, belonging to psycho-sexology and sexual medicine, has been due to its still unclear aetiology, nature, and its manifestation in relationship with several organic and psychopathological conditions. So, the specialist (the psychologist, psychiatrist, endocrinologist, neurologist) may encounter some difficulties in diagnosing and managing this symptom. The first main objective of this position statement, which has been developed in collaboration between the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Psychopathology (SOPSI) is to give to the reader evidence about the necessity to consider hypersexuality as a symptom related to another underlying condition. Following this consideration, the second main objective is to give specific statements, for the biopsychosocial assessment and the diagnosis of hypersexual behavior, developed on the basis of the most recent literature evidence. To develop a psycho-pharmacological treatment tailored on patients' needs, our suggestion is to assess the presence of specific comorbid psychopathological and organic conditions, and the impact of pharmacological treatments on the presence of an excess of sexual behavior. Finally, a suggestion of a standardized psychometric evaluation of hypersexuality will be given.

Axillary nodal involvement by primary tumor features in early breast cancer: an analysis of 2600 patients.

BACKGROUND: Primary tumor characteristics, which are readily available to all clinicians, may aid in selecting the optimal adjuvant therapy for patients with breast cancer (BC). Herein, we investigated the relationship between tumor size, hormone receptor and HER2 status, Ki67 and age with axillary lymph node metastases (ALNM) in early-BC patients. METHODS: We analyzed data on consecutive 2600 early-BC cases collected in the registry of Fondazione IRCC Istituto Nazionale dei Tumori, Milano, Italy. Correlation between Ki67 and primary tumor size (T-size) was calculated by Spearman's rank correlation coefficient. Association of ALNM with Ki67 and other tumor characteristics was investigated by logistic regression. Adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated in all cases, and separately analyzed according to age, T-size and BC subtype. RESULTS: Large tumor size strongly associated to ALNM, with an adjusted odds ratio (OR) for each 5-mm increase of 1.32 (95% CI 1.24-1.41), except for triple-negative BC (TNBC) cases. In tumors =10 mm, without lymphovascular invasion, representing the strongest predictor of ALNM (OR 6.09, 95% CI 4.93-7.53), Ki67 resulted particularly informative, with a fourfold increased odds of ALNM for values > 30%. CONCLUSIONS: These results raise the question whether axillary node status is redundant in cases with exceptionally good features, i.e., small tumors with low Ki67, or in those candidate to adjuvant systemic treatment/radiotherapy anyway including TNBC, and support the incorporation of primary BC tumor characteristics as stratification factors in ongoing trials aiming at de-escalating axillary surgical procedures.

Absolute basophil count is associated with time to recurrence in patients with high-grade T1 bladder cancer receiving bacillus Calmette-Guérin after transurethral resection of the bladder tumor.

BACKGROUND: Basophils, eosinophils and monocytes may be involved in BCG-induced immune responses and be associated with outcomes of bladder cancer patients receiving intravesical BCG. Our objective was to explore the association of baseline counts of basophils, eosinophils and monocytes with outcomes of patients with high-grade T1 bladder cancer receiving a standard course of intravesical BCG. METHODS: We retrospectively reviewed medical records of patients with primary T1 HG/G3 bladder cancer. After re-TURBT, patients were treated with a 6-week course of intravesical BCG induction followed by intravesical BCG every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months from initiation of therapy The analysis of potential risk factors for recurrence, muscle invasion and cancer-specific and overall survival was performed using univariable Cox regression models. Those factors that presented, at univariate analysis, an association with the event at a liberal p < 0.1, have been selected for the development of a multivariable model. RESULTS: A total of 1045 patients with primary T1 HG/G3 were included. A total of 678 (64.9%) recurrences, 303 (29.0%) progressions and 150 (14.3%) deaths were observed during follow-up. Multivariate analysis showed that logarithmic transformation of basophils count was associated with a 30% increment in the hazard of recurrence per unit increase of logarithmic basophils count (HR 1.30; 95% confidence interval 1.09-1.54; p = 0.0026). Basophil count modeled by quartiles was also significantly associated with time to recurrence [second vs. lower quartile HR 1.42 (1.12-1.79); p = 0.003, third vs. lower quartile HR 1.26 (1.01-1.57); p = 0.041; upper vs. lower quartile HR 1.36 (1.1-1.68); p = 0.005]. The limitations of a retrospective study are applicable. CONCLUSION: Baseline basophil count may predict recurrence in BCG-treated HG/G3 T1 bladder cancer patients. External validation is warranted.

Hysteroscopic Treatment of Primary Endometrial Marginal Zone B-cell Lymphoma (MALToma).

Primary extranodal marginal zone B-cell lymphomas (MALToma) of the endometrium are rare tumors. We report a case of MALToma diagnosed within an endometrial polyp in a patient presenting with postmenopausal vaginal bleeding. The patient underwent a conventional hysteroscopic procedure for intrauterine polyps. There was no suspicion of malignancy during the preoperative investigations or at surgery. Conventional bipolar resection of the polyps was performed. The present case demonstrates that conservative management of endometrial MALToma may be considered as a safe alternative to hysterectomy. Further data on long-term follow up is needed to confirm the safety of this conservative approach.

Familial aggregation of MATRICS Consensus Cognitive Battery scores in a large sample of outpatients with schizophrenia and their unaffected relatives.

BACKGROUND: The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative-control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands' scores. METHODS: Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands' MCCB scores predicted REL neurocognitive performance. RESULTS: SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning. CONCLUSIONS: In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors.

Epigenetic control of gene expression: Potential implications for cancer treatment.

Epigenetic changes are defined as inherited modifications that are not present in DNA sequence. Gene expression is regulated at various levels and not only in response to DNA modifications. Examples of epigenetic control are DNA methylation, histone deacetylation and mi-RNA expression. Methylation of several tumor suppressor gene promoters is responsible for their silencing and thus potentially sustain cancerogenesis. Similarly, histone deacetylation can lead to oncogene activation. mi-RNA are small (18-20 nucleotides) non-coding RNA fragments capable of inhibiting other m-RNA, ultimately altering the balance in oncogene and tumor suppressor gene expression. It has been shown that growth of several tumor types can be stimulated by epigenetic changes in various phases of cancerogenesis, and drugs able to interfere with these mechanisms can have a positive impact on tumor progression. As matter of fact, epigenetic changes are dynamic and can be reversed by epigenetic inhibitors. Recently, methyltransferase and histone deacetylase inhibitors have attracted the attention of researchers and clinicians as they potentially provide alternative therapeutic options in some cancers. Drugs that inhibit DNA methylation or histone deacetylation have been studied for the reactivation of tumor suppressor genes and repression of cancer cell growth. Epigenetic inhibitors work alone or in combination with other therapeutic agents. To date, a number of epigenetic inhibitors have been approved for cancer treatment. The main challenge in the field of epigenetic inhibitors is their lack of specificity. In this review article we describe their mechanisms of action and potential in cancer treatment.

KIR2DL3 and the KIR ligand groups HLA-A-Bw4 and HLA-C2 predict the outcome of hepatitis B virus infection.

Killer immunoglobulin-like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly polymorphic, and certain HLA-KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty-seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA-A-Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA-C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA-A-Bw4 and HLA-C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection.

Efficacy of allergen immunotherapy in reducing the likelihood of developing new allergen sensitizations: a systematic review.

BACKGROUND: Guidelines and position papers indicate that allergen immunotherapy (AIT) is the only disease-modifying treatment, including prevention of the onset of new allergen sensitizations. However, this preventive effect was shown by only a few observational studies. Our aim was to systematically review the efficacy of AIT in preventing the onset of new allergen sensitizations. METHODS: Computerized bibliographic searches of Medline, EMBASE, and the Cochrane Library (through June 2015) were supplemented with manual searches of reference lists. Observational studies or randomized controlled trials with a long-term observation period were included. Paired reviewers extracted data about study characteristics and assessed biases. The end point was the risk difference in the onset of new allergen sensitizations between patients treated with AIT and pharmacotherapy. The strength of the evidence was graded based on the risk of bias, consistency, and magnitude of effect, according to the GRADE Working Group's guide. RESULTS: Eighteen studies (1049 children, 10 057 adults) met the inclusion criteria. The risk of bias was high in all but one study. Low evidence supports the position that AIT prevents the onset of new allergen sensitizations, with 10 of 18 studies reporting a reduction in the onset of new sensitizations in patients treated with AIT vs placebo. Small studies and studies with a shorter follow-up showed the highest benefit of AIT. CONCLUSIONS: The overall evidence provides a low-grade level of the evidence supporting the efficacy of AIT in preventing the onset of new allergen sensitizations, but high-quality studies could change this estimate.

Cross-cultural and socio-demographic correlates of homophobic attitude among university students in three European countries.

PURPOSE: The aim of this study was to investigate homophobic attitudes in three European countries: Italy, Albania, and Ukraine. One thousand and forty-eight students were recruited in Italian (n = 766), Albanian (n = 180), and Ukrainian (n = 102) university centers. METHODS: A socio-demographic questionnaire and Homophobia Scale (HS) were administered by our staff. RESULTS: Cross-cultural and significant differences among Italian, Albanian, and Ukrainian students were found on the Homophobia Scale (HS; Italy: mean = 22.26 ± 16.73; Albania: mean = 38.15 ± 17.28; Ukraine: mean = 59.18 ± 16.23). The analysis of socio-demographic characteristics revealed that the male gender emerged as main predictor of homophobic attitude in all the three countries, although also a conservative political orientation and the religious belief predict higher homophobia levels in Italy and Albania, particularly. CONCLUSIONS: This study revealed that in these European countries assessed, attitudes toward homosexuality are different. Ukrainians display higher levels of homophobia than Albanians and Italians, confirming the central role of cultural differences in homophobic attitudes. Nevertheless, some socio-demographic aspects such as identification as male have a similar influence on homophobic attitudes in all assessed populations.

Allergy immunotherapy across the life cycle to promote active and healthy ageing: from research to policies: An AIRWAYS Integrated Care Pathways (ICPs) programme item (Action Plan B3 of the European Innovation Partnership on active and healthy ageing) and the Global Alliance against Chronic Respiratory Diseases (GARD), a World Health Organization GARD research demonstration project.

Allergic diseases often occur early in life and persist throughout life. This life-course perspective should be considered in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old age adults. The current paper was developed by a working group of AIRWAYS integrated care pathways for airways diseases, the model of chronic respiratory diseases of the European Innovation Partnership on active and healthy ageing (DG CONNECT and DG Santé). It considered (1) the political background, (2) the rationale for allergen immunotherapy across the life cycle, (3) the unmet needs for the treatment, in particular in preschool children and old age adults, (4) the strategic framework and the practical approach to synergize current initiatives in allergen immunotherapy, its mechanisms and the concept of active and healthy ageing.

Impact of Prior Platinum-Based Therapy on Patients Receiving Salvage Systemic Treatment for Advanced Urothelial Carcinoma.

BACKGROUND: Trials of salvage therapy for advanced urothelial carcinoma have required prior platinum-based therapy. This practice requires scrutiny because non-platinum-based first-line therapy may be offered to cisplatin-ineligible patients. PATIENTS AND METHODS: Data of patients receiving salvage systemic chemotherapy were collected. Data on prior first-line platinum exposure were required in addition to treatment-free interval, hemoglobin, Eastern Cooperative Oncology Group performance status, albumin, and liver metastasis status. Cox proportional hazard regression was used to evaluate their association with overall survival (OS) after accounting for salvage single-agent or combination chemotherapy. RESULTS: Data were obtained from 455 patients previously exposed to platinum-based therapy and 37 not exposed to platinum. In the group exposed to prior platinum therapy, salvage therapy consisted of a single-agent taxane (n = 184) or a taxane-containing combination chemotherapy (n = 271). In the group not exposed to prior platinum therapy, salvage therapy consisted of taxane or vinflunine (n = 20), 5-fluorouracil (n = 1), taxane-containing combination chemotherapy (n = 12), carboplatin-based combinations (n = 2), and cisplatin-based combinations (n = 2). The median OS for the prior platinum therapy group was 7.8 months (95% confidence interval, 7.0, 8.1), and for the group that had not received prior platinum therapy was 9.0 months (95% confidence interval, 6.0, 11.0; P = .50). In the multivariable analysis, prior platinum therapy versus no prior platinum exposure did not confer an independent impact on OS (hazard ratio, 1.10; 95% confidence interval, 0.75, 1.64; P = .62). CONCLUSION: Prior platinum- versus non-platinum-based chemotherapy did not have a prognostic impact on OS after accounting for major prognostic factors in patients receiving salvage systemic chemotherapy for advanced urothelial carcinoma. Lack of prior platinum therapy should not disqualify patients from inclusion onto trials of salvage therapy.

AllAboard: Visual Exploration of Cellphone Mobility Data to Optimise Public Transport.

The deep penetration of mobile phones offers cities the ability to opportunistically monitor citizens' mobility and use data-driven insights to better plan and manage services. With large scale data on mobility patterns, operators can move away from the costly, mostly survey based, transportation planning processes, to a more data-centric view, that places the instrumented user at the center of development. In this framework, using mobile phone data to perform transit analysis and optimization represents a new frontier with significant societal impact, especially in developing countries. In this paper we present AllAboard, an intelligent tool that analyses cellphone data to help city authorities in visually exploring urban mobility and optimizing public transport. This is performed within a self contained tool, as opposed to the current solutions which rely on a combination of several distinct tools for analysis, reporting, optimisation and planning. An interactive user interface allows transit operators to visually explore the travel demand in both space and time, correlate it with the transit network, and evaluate the quality of service that a transit network provides to the citizens at very fine grain. Operators can visually test scenarios for transit network improvements, and compare the expected impact on the travellers' experience. The system has been tested using real telecommunication data for the city of Abidjan, Ivory Coast, and evaluated from a data mining, optimisation and user prospective.

The use of illicit drugs as self-medication in the treatment of cluster headache: Results from an Italian online survey.

BACKGROUND: Cluster headache (CH) patients often receive unsatisfactory treatment and may explore illicit substances as alternatives. We aimed to explore this use of illicit drugs for CH treatment. METHODS: We invited CH patients from an Internet-based self-help group to complete a questionnaire regarding their therapeutic use of illicit substances. RESULTS: Of the 54 respondents, 29 were classified as chronic and 39 were drug-resistant cases. Fifty patients had previously tried subcutaneous sumatriptan, 40 had tried O2, and 48 had tried at least one prophylactic treatment. All 54 patients specified that they were dissatisfied with conventional treatments. Thirty-four patients had used cannabinoids, 13 cocaine, 8 heroin, 18 psilocybin, 12 lysergic acid amide (LSA), and 4 lysergic acid diethylamide (LSD). DISCUSSION: Some patients with intractable CH decided to try illicit drugs concomitantly with cessation of medical care. Most of these patients found suggestions for illicit drug use on the Internet. Many patients seemed to underestimate the judicial consequences of, and had an overestimated confidence in the safety of, such illicit treatments. Physicians are often not informed by patients of their choice to use illicit drugs. This leads to questions regarding the true nature of the physician-patient relationship among dissatisfied CH patients.

Effect of multiple honey doses on non-specific acute cough in children. An open randomised study and literature review

BACKGROUND: Honey is recommended for non-specific acute paediatric cough by the Australian guidelines. Current available randomised clinical trials evaluated the effects of a single evening dose of honey, but multiple doses outcomes have never been studied. OBJECTIVES: To evaluate the effects of wildflower honey, given for three subsequent evenings, on non-specific acute paediatric cough, compared to dextromethorphan (DM) and levodropropizine (LDP), which are the most prescribed over-the-counter (OTC) antitussives in Italy. METHODS: 134 children suffering from non-specific acute cough were randomised to receive for three subsequent evenings a mixture of milk (90 ml) and wildflower honey (10 ml) or a dose of DM or LDP adjusted for the specific age. The effectiveness was evaluated by a cough questionnaire answered by parents. Primary end-point efficacy was therapeutic success. The latter was defined as a decrease in cough questionnaire score greater than 50% after treatment compared with baseline values. RESULTS: Three children were excluded from the study, as their parents did not complete the questionnaire. Therapeutic success was achieved by 80% in the honey and milk group and 87% in OTC medication group (p = 0.25). CONCLUSIONS: Milk and honey mixture seems to be at least as effective as DM or LDP in non-specific acute cough in children. These results are in line with previous studies, which reported the health effects of honey on paediatric cough, even if placebo effect cannot be totally excluded

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Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis.

BACKGROUND: First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. PATIENTS AND METHODS: Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2 → 2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. RESULTS: In group 4/2 → 2/1, the overall incidence of grade ≥ 3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥ 3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2 → 2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. CONCLUSIONS: mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.