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Objective In this review, we aim to collect and discuss available data about the role and composition of tumor microenvironment (TME) in oligometastatic (OMD) and oligoprogressive (OPD) non-small cell lung cancer (NSCLC). Furthermore, we aim to summarize the ongoing clinical trials evaluating as exploratory objective the TME composition, through tissue and/or blood samples, in order to clarify whether TME and its components could explain, at least partially, the oligometastatic/oligoprogressive process and could unravel the existence of predictive and/or prognostic factors for local ablative therapy (LAT). Background OMD/OPD NSCLC represent a heterogeneous group of diseases. Several data have shown that TME plays an important role in tumor progression and therefore in treatment response. The crucial role of several types of cells and molecules such as immune cells, cytokines, integrins, protease and adhesion molecules, tumor-associated macrophages (TAMs) and mesenchymal stem cells (MSCs) has been widely established. Due to the peculiar activation of specific pathways and expression of adhesion molecules, metastatic cells seem to show a tropism for specific anatomic sites (the so-called "seed and soil" hypothesis). Based on this theory, metastases appear as a biologically driven process rather than a random release of cancer cells. Although the role and the function of TME at the time of progression in patients with NSCLC treated with tyrosine-kinase inhibitors and immune checkpoint inhibitors (ICIs) have been investigated, limited data about the role and the biological meaning of TME are available in the specific OMD/OPD setting. Methods Through a comprehensive PubMed and ClinicalTrials.gov search, we identified available and ongoing studies exploring the role of TME in oligometastatic/oligoprogressive NSCLC. Conclusions Deepening the knowledge on TME composition and function in OMD/OPD may provide innovative implications in terms of both prognosis and prediction of outcome in particular from local treatments, paving the way for future investigations of personalized approaches in both advanced and early disease settings.

Background Improvement in radiotherapy techniques and expected outcomes, as well as in understanding the underlying biological mechanisms contributing to its action (immunomodulation in primis), led to the integration of this therapeutical approach in the current management of advanced non-small cell lung cancer (NSCLC), not only in oncogene-driven tumors, but also in non-oncogene addicted NSCLC where the combination of platinum-based chemotherapy plus pembrolizumab represents nowadays the pivotal strategy. In this light, we have designed a randomized phase II (ESPERa) trial to evaluate the efficacy and safety of adding Stereotactic Body Radiotherapy (SBRT) to pembrolizumab-pemetrexed maintenance in advanced NSCLC patients experiencing disease response or stability after chemo-immunotherapy induction. Patients and Methods Advanced non-oncogene addicted NSCLC patients with ECOG performance status of 0 or 1, who obtained disease response or stability after 4 cycles of platinum-based chemotherapy plus pembrolizumab will be randomized 2:1 to receive pembrolizumab-pemetrexed maintenance plus SBRT vs pembrolizumab-pemetrexed alone. The primary endpoint is progression-free survival (PFS). Concomitant translational researches will be performed to identify potential prognostic and/or predictive biomarkers, as well as to analyze and monitor tumour microenvironment and tumor-host interactions. Conclusions Although available data suggest the safety and efficacy of combining immunotherapy and radiotherapy, their systematic integration in the current first-line landscape still remains to be explored. If the pre-planned endpoints of the ESPERa trial will be achieved, the addition of SBRT to pembrolizumab-pemetrexed maintenance as a strategy to consolidate and ideally improve the awaited benefit could be considered as a promising strategy in NSCLC undergoing first-line therapy, as well as an interesting approach to be evaluated in other disease setting, as well as in other oncological malignancies where immunotherapy represents nowadays the standard-of-care.

Infectious diseases represent a relevant issue in lung cancer patients. Bacterial and viral infections might influence the patients’ prognosis, both directly affecting the immune system and indirectly impairing the outcome of anticancer treatments, mainly immunotherapy. In this analysis, we aimed to review the current evidence in order to clarify the complex correlation between infections and lung cancer. In detail, we mainly explored the potential impact on immunotherapy outcome/safety of (1) bacterial infections, with a detailed focus on antibiotics; and (2) viral infections, discriminating among (a) human immune-deficiency virus (HIV), (b) hepatitis B/C virus (HBV-HCV), and (c) Sars-Cov-2. A series of studies suggested the prognostic impact of antibiotic therapy administration, timing, and exposure ratio in patients treated with immune checkpoint inhibitors, probably through an antibiotic-related microbiota dysbiosis. Although cancer patients with HIV, HBV, and HCV were usually excluded from clinical trials evaluating immunotherapy, some retrospective and prospective trials performed in these patient subgroups reported similar results compared to those described in not-infected patients, with a favorable safety profile. Moreover, patients with thoracic cancers are particularly at risk of COVID-19 severe outcomes and mortality. Few reports speculated about the prognostic implications of anticancer therapy, including immunotherapy, in lung cancer patients with concomitant Sars-Cov-2 infection, showing, to date, inconsistent results. The correlation between infectious diseases and immunotherapy remains to be further explored and clarified in the context of dedicated trials. In clinical practice, the accurate and prompt multidisciplinary management of lung cancer patients with infections should be encouraged in order to select the best treatment options for these patients, avoiding unexpected toxicities, while maintaining the anticancer effect.

Background The aetiology of Parkinson’s disease (PD) is still very controversial, with a peculiar lack of established risk factors or protective behavior. Methods We carried out a case–control study of 634 idiopathic PD patients admitted from 2011 to 2015 to two hospitals located in central Italy and 532 controls matched by hospital, gender and age (± 5 years). The study questionnaire included questions on host factors, family history, residence, occupation and lifestyle. Odds ratios (ORs) for PD and 95% confidence intervals (CIs) were estimated with logistic regression, adjusting for actual and potential confounders. Results A lower OR was observed in females (0.74; 95%CI:0.58–0.96), while older age classes showed a constantly increased risk for PD (p Conclusions The results from this study confirmed the higher risk of PD in males and in elderly, and the inverse association with smoking habit. The possible etiological role of familial clustering, dietary habit, and some job tasks is suggested.

Background: On February 23rd the first case of SARS-CoV-2 infection was diagnosed at the University Hospital Trust of Verona, Italy On March 13th, the Oncology Section was converted into a 22 inpatient beds COVID unit and we had to reshape our organization and personnel to face the SARS-CoV-2 epidemic, while maintaining our oncological activity Methods: We tracked down oncological activity from January 1st to March 31st, 2020, in relationship to the organizational changes implemented and in comparison to the same period of 2019 We also recorded cases of SARS-CoV-2 infections observed in oncology health professionals and hospital admissions of active oncology patients for SARS-CoV-2 infection Results: Progressive restrictions in patients', visitors', and caregivers' access to the inpatient and outpatient facilities of the Oncology section and organizational changes were adopted early on during the epidemic peak Since March 13th, segregated personnel teams were created, one dedicated to the COVID unit and a "clean" one dedicated to oncological patients, resulting in an overall 40% and 43% reduction in oncology-dedicated medical and nursing/auxiliary staff, respectively As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations, and specialty visits in the period January-March 2020 was 8%, 6%, and 3%, respectively;based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11 Patient's acceptance of adopted measures was very high (see abstract by Tregnago D) Overall, 8/85 (9%) health professionals tested positive for SARS-CoV-2 (no hospital admissions and no treatment required) and 7/525 (1 3%) active oncology patients were admitted for SARS-CoV-2 infection (of whom, 2 died of infection-related complications) Conclusions: A minimal (

Background: The health emergency caused by the SarS-Cov-2 pandemic has a strong impact on oncological patients' (pts) life. The purpose of this study is to explore the emotional impact and pts' perception experienced who accessed to our Oncology section at University Hospital and Trust of Verona (Italy) regarding these rules. Method(s): An questionnaire was designed by our Psycho-Oncology service and administered to all pts accessing to our outpatient facilities during a 21-days period (April 9th - April 30th, 2020). Two main areas were investigated: i) organizational aspects and ii) awareness about infection risks, protective strategies, and new rules adopted (14 items, plus demographic data). Percentage of relevant answers to questionnaire items are reported with 95% confidence intervals (95% CI). Result(s): Among 241 respondents, fear of accessing hospital facilities and that chemotherapy treatment could increase the infection risk was reported to be quite high or high in 34% (95% CI: 29-41%) and 27% (95% CI: 21-33%), respectively. Awareness of disease-related risks of infection and strategies to reduce them was "very clear" or "fairly clear" [83% (95% CI: 78-88%) and 93% (95% CI: 90-96%), respectively]. Availability of medical personnel to be contacted while not in hospital was perceived as "very high". Almost all pts felt that organizational measures were clearly expressed (98%, 95% CI: 96-100%) and mainly obtained through the information received at the triage (73%, 95% CI: 67-79%). Overall acceptance of these measures was very high (>70%). Of note, the acceptance of phone-based follow-up and visits were perceived as "not very adequate" or "absolutely not adequate" by 17% (95% CI: 12-22 %) and 18% (95% CI: 13-23%) of respondents, respectively. Conclusion(s): Herein, we report among the first real-life experiences about oncological pts' perception of infection risks and their level of acceptance of protective measures during SarS-Cov-2 pandemic. A timely and thoughtful measures adoption, the coordinated efforts of all figures involved in cancer care and an effective communication strategy to share the necessary risks and sacrifices with pts/caregivers, can lead to effective protection of oncological pts. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: All authors have declared no conflicts of interest.Copyright © 2020

Background and purpose When switching between monoamine oxidase type B (MAO-B) inhibitors, a 15-day suspension period is a precautionary measure to avoid a serotonin syndrome and hypertensive crisis. However, this indication results in a major inconvenience for parkinsonian patients because of the worsening of their clinical condition. In routine clinical practice, neurologists often perform a substitution of these two drugs without solution of continuity (i.e. overnight), to avoid worsening of fluctuations and prolonged OFF periods. Therefore, a safety open label study was performed to investigate the possible risks of switching overnight from rasagiline to safinamide. Methods The study population included 20 advanced patients with Parkinson's disease on stable treatment with rasagiline and levodopa (alone or in combination with other anti-parkinsonian medication). The possible occurrence of serotonin syndrome and hypertension was monitored through a strict clinical observation and a 24-h Holter recording (ABPM) performed twice, whilst subjects were on rasagiline and immediately after switching to safinamide. Results No cases of serotonin syndrome or hypertensive crisis occurred during the study. Changes that were not significant occurred in the primary end-point: 24-h mean blood pressure (BP) had a mild +4.4% increase in the ABPM2 versus ABPM1 (P = 0.17), 24-h systolic and diastolic BP values were slightly higher at ABPM2 compared to ABPM1 (respectively +3.3%, P = 0.13; and 5.4%, P = 0.08) and 24-h systolic BP variability was unchanged between the two ABPM evaluations (from 8.6 ± 2.9 to 8.9 ± 1.8; P = 0.27). Conclusion The results of the present study confirm that the overnight switch from rasagiline to safinamide is safe and well tolerated by patients.

Lung cancer remains the leading cause of cancer‐related death worldwide. Affected patients frequently experience debilitating disease‐related symptoms, including dyspnea, cough, fatigue, anxiety, depression, insomnia, and pain, despite the progresses achieved in term of treatment efficacy. Physical activity and exercise are nonpharmacological interventions that have been shown to improve fatigue, quality of life, cardiorespiratory fitness, pulmonary function, muscle mass and strength, and psychological status in patients with lung cancer. Moreover, physical fitness levels, especially cardiorespiratory endurance and muscular strength, are demonstrated to be independent predictors of survival. Nevertheless, patients with lung cancer frequently present insufficient levels of physical activity and exercise, and these may contribute to quality of life impairment, reduction in functional capacity with skeletal muscle atrophy or weakness, and worsening of symptoms, particularly dyspnea. The molecular bases underlying the potential impact of exercise on the fitness and treatment outcome of patients with lung cancer are still elusive. Counteracting specific cancer cells’ acquired capabilities (hallmarks of cancer), together with preventing treatment‐induced adverse events, represent main candidate mechanisms. To date, the potential impact of physical activity and exercise in lung cancer remains to be fully appreciated, and no specific exercise guidelines for patients with lung cancer are available. In this article, we perform an in‐depth review of the evidence supporting physical activity and exercise in lung cancer and suggest that integrating this kind of intervention within the framework of a global, multidimensional approach, taking into account also nutritional and psychological aspects, might be the most effective strategy. Implications for Practice Although growing evidence supports the safety and efficacy of exercise in lung cancer, both after surgery and during and after medical treatments, most patients are insufficiently active or sedentary. Engaging in exercise programs is particularly arduous for patients with lung cancer, mainly because of a series of physical and psychosocial disease‐related barriers (including the smoking stigma). A continuous collaboration among oncologists and cancer exercise specialists is urgently needed in order to develop tailored programs based on patients’ needs, preferences, and physical and psychological status. In this regard, benefit of exercise appears to be potentially enhanced when administered as a multidimensional, comprehensive approach to patients’ well‐being., The potential effect of physical activity in lung cancer is not fully understood, and no specific exercise guidelines for lung cancer patients are available. This article reviews the evidence supporting physical activity and exercise in lung cancer and suggests that this type of intervention, along with considerations for the nutritional and psychological aspects of such an intervention, might be the most effective strategy.

Background: The health emergency caused by the SarS-Cov-2 pandemic has been strongly impacting on oncological patients’ (pts). The purpose of this study was to explore the emotional impact and perception of cancer pts who received the vaccine against COVID-19 at the University Hospital and Trust of Verona (Italy). Methods: After the first dose of COVID-19 vaccine an anonymously questionnaire was proposed to cancer pts (March-May 2021). The survey investigated anxiety and depression levels using the Hospital Anxiety and Depression Scale (HADS), psychological distress with the Distress Thermometer (DT). Additionally, four specific items regarding the awareness about: i) infection risks, ii) interference with chemotherapy treatment, and iii) adverse effects, were developed. Descriptive analyses were performed. Results: A total of 736 patients (mean age 63 yrs) completed the questionnaire. Breast (23%) and gastrointestinal (40%) were the most represented cancer sites. The majority of pts (65%) reported mild levels of distress (DT ≤4), while moderate (DT 5-7) and severe (DT ≥8) levels were identified in 26% and 9% of participants, respectively. A total of 11% and 8% of pts experienced clinically significant symptoms of anxiety and depression (HADS ≥11), whereas 15% were borderline (HADS score 8-10). Two thirds of pts (67%) thought that the vaccination may reduce the infection risks and 56% felt safer. Overall, 59% of pts did not believe that vaccine-related side effects may interfere with the oncological treatment and 49% considered the vaccination safe. Conclusions: Most cancer pts undergoing COVID-19 vaccination presented mild levels of anxiety, depression and distress. Oncological pts undergoing vaccination felt safe and judged the benefits of COVID-19 vaccination to overweight the potential side effects. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Aims While several generic preparations of levodopa/carbidopa and levodopa/benserazide (LBD) are currently available, pharmacokinetic (PK) equivalence and therapeutic equivalence studies with levodopa generics are not available in Italy. Lack of data on generic formulations is a critical factor for their limited use in this country and often lead patients to refuse the generic version of the branded drug. Methods An experimental, 2-centre, randomized, double-blind, 2-sequence, noninferiority cross-over study was designed to evaluate both the PK equivalence and clinical equivalence of multiple doses of the generic preparation of LDB, Teva Italia, compared to the originator (Madopar). Forty-three out-patients with a diagnosis of idiopathic Parkinson's disease on LDB, were recruited and randomly assigned to 1 of 2 study sequences: generic-originator or originator-generic. Clinical evaluations were performed at the end of each study period. A PK study with an LDB fixed dose (100 + 25 mg) was performed in a subpopulation of 14 subjects. Results Clinical data showed a reduction of 0.49 and 1.54 in the mean UPDRS III scores for the LDB and the originator, respectively. The 95% CIs [-2.21: 0.11] of the mean difference original vs LDB are smaller than the clinically significant difference of 3 UPDRS III points, supporting the conclusion that the treatment with LDB is not inferior to the originator. No statistically significant differences were found with respect to area under the curve to last dose, half-life, maximum concentration, time to maximum concentration and last observed concentration. Conclusion These findings prove the therapeutic clinical equivalence as well the PK equivalence of the generic LDB and the originator (Madopar).

Introduction Software-based measurements of postural abnormalities in Parkinson's disease (PD) are the gold standard but may be time-consuming and not always feasible in clinical practice. Wall goniometer (WG) is an easier, quicker, and inexpensive instrument for screening patients with postural abnormalities, but no studies have investigated its validity so far. The aim of this study was to investigate the validity of the WG to measure postural abnormalities. Methods A total of 283 consecutive PD outpatients with ≥5° forward trunk, lateral trunk or forward neck bending (FTB, LTB, FNB, respectively) were recruited from seven centers for movement disorders. Postural abnormalities were measured in lateral and posterior view using a freeware program (gold standard) and the WG. Both angles were expressed in degrees (°). Sensitivity and specificity for the diagnosis of camptocormia, Pisa syndrome, and anterocollis were assessed. Results WG showed good to excellent agreement (intraclass correlation coefficient from 0.80 to 0.98) compared to the gold standard. Bland-Altman plots showed a mean difference between the methods from −7.4° to 0.4° with limits of agreements from −17.7° to 9.5°. Sensitivity was 100% for the diagnosis of Pisa syndrome, 95.74% for anterocollis, 76.67% for upper camptocormia, and 63.64% for lower camptocormia. Specificity was 59.57% for Pisa syndrome, 71.43% for anterocollis, 89.80% for upper camptocormia, and 100% for lower camptocormia. Overall, the WG underestimated measurements, especially in lower camptocormia with an average of −8.7° (90% of cases). Conclusion WG is a valid tool for screening Pisa syndrome and anterocollis, but approximately 10° more should be added for camptocormia.

New treatments based on peripheral stimulation of the sensory–motor system have been inspiring new rehabilitation approaches in Parkinson’s disease (PD), especially to reduce gait impairment, levodopa washout effects, and the incidence of falls. The aim of this study was to evaluate the change in gait and the clinical status of PD patients after six sessions of a treatment based on automated mechanical peripheral stimulation (AMPS). Eighteen patients with PD and 15 age-matched healthy individuals (control group) participated in this study. A dedicated medical device delivered the AMPS. PD patients were treated with AMPS six times once every 4 days. All PD patients were treated in the off-levodopa phase and were evaluated with gait analysis before and after the first intervention (acute phase), after the sixth intervention, 48 h after the sixth intervention, and 10 days after the end of the treatment. To compare the differences among the AMPS interventions (pre, 6 AMPS, and 10 days) in terms of clinical scales, a t-test was used (α≤0.05). In addition, to compare the differences among the AMPS interventions (pre, post, 6 AMPS, 48 h and 10 days), the gait spatiotemporal parameters were analyzed using the Friedman test and the Bonferroni post-hoc test (α≤0.05). Also, for comparisons between the PD group and the control group, the gait spatiotemporal parameters were analyzed using the Mann–Whitney test and the Bonferroni post-hoc test (α≤0.05). The results of the study indicate that the AMPS treatment has a positive effect on bradykinesia because it improves walking velocity, has a positive effect on the step and stride length, and has a positive effect on walking stability, measured by the increase in stride length. These results are consistent with the improvements measured with clinical scales. These findings indicate that AMPS treatment seems to generate a more stable walking pattern in PD patients, reducing the well-known gait impairment that is typical of PD; regular repetition every 4 days of AMPS treatment appears to be able to improve gait parameters, to restore rhythmicity, and to reduce the risk of falls, with benefits maintained up to 10 days after the last treatment. The trial was registered online at ClinicalTrials.gov (number identifier: NCT0181528).