Successful treatment with selpercatinib after pralsetinib-related pneumonitis and intracranial failure in a patient with RET-rearranged nonsmall cell lung cancer.

Pralsetinib and selpercatinib are two highly potent and selective rearranged during transfection (RET) inhibitors that substantially improved the clinical outcome of patients with RET-rearranged non-small cell lung cancer. Treatment with one RET inhibitor after failure of the other is generally not recommended because of cross-resistance mechanisms. We report the case of a patient affected by metastatic RET-rearranged non-small cell lung cancer who experienced long-lasting disease control with pralsetinib. After 13 months from treatment start, the patient developed recurrent drug-related pneumonitis, requiring temporary interruptions and dose reductions and eventually failing to control the disease. Selpercatinib was then started as an off-label treatment, allowing both clinical and radiological intracranial disease control. Selpercatinib was well-tolerated at full dosage, and no pulmonary event occurred. In our case report, after pralsetinib dose reduction due to pulmonary toxicity, the therapeutic switch to selpercatinib allowed the patient to receive a full-dose treatment, eventually restoring disease control. Our case report and a few literature data suggest that switching from pralsetinib to selpercatinib may represent a therapeutic opportunity, especially for patients with brain metastases.

Physical Activity and Exercise in Lung Cancer Care: Will Promises Be Fulfilled?

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.

Infections and Immunotherapy in Lung Cancer: A Bad Relationship?

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.

Clinical and pharmacokinetics equivalence of multiple doses of levodopa benserazide generic formulation vs the originator (Madopar).

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).

Clinical assessment of a new wearable tool for continuous and objective recording of motor fluctuations and ON/OFF states in patients with Parkinson's disease.

Clinical rating scales typically includes subjective evaluations, and their time-limited duration may fail to capture daily fluctuations in motor symptoms resulting from Parkinson's disease (PD). Recently, a new tool (i.e. the PD-Watch) has been proposed for the objective and continuous assessment of PD motor manifestations based on evaluating frequency data from a wrist-worn tri-axial accelerometer and identifying specific movement patterns typically associated with disorders. This reduces the probability of confusing physiological or pathological movements occurring at the same frequency. In this work, we present a new method for assessing motor fluctuations through a wrist-worn accelerometer. We also explore the agreement between the continuous data generated by the proposed method and data reported in the patient diaries. In this study, twelve PD patients were recruited with an overall recording duration of 528 hours. Results of this preliminary study show that the proposed tool has suitable and adequate performances for analysing the motor signs of PD patients, and the estimated sensitivity, specificity, and accuracy of the tool are 85%, 94%, and 91%, respectively.

Therapeutic education for empowerment and engagement in patients with Parkinson's disease: A non-pharmacological, interventional, multicentric, randomized controlled trial.

Background: In 1997 the European Parkinson's Disease Associations launched the Charter for People with Parkinson's disease that stated the right of patients to be informed and trained on the disease, its course, and treatments available. To date, few data analyzed the effectiveness of education program on motor and non-motor symptoms of PD. Objective: The aim of this study was to evaluate the efficacy of an education program as it was a pharmacological treatment, thus choosing as the primary endpoint the change in daily OFF hours, the most widely used outcome in pharmaceutical clinical trials on PD patients with motor fluctuations. Secondary outcomes were change in motor and non-motor symptoms, quality of life and social functioning. The long-term efficacy of the education therapy was also evaluated by analyzing data collected at 12- and 24-weeks follow-up outpatient visits. Methods: One hundred and twenty advanced patients and their caregivers were assigned to the intervention or control group in a single-blind, multicentric, prospective, randomized study evaluating an education program structured in individual and group sessions over a 6-weeks period.At the end of study, the intervention group showed a significant reduction in daily OFF hours compared to control patients (-1.07 ± 0.78 vs. 0.09 ± 0.35, p < 0.0001) and a significant improvement was also reported in most secondary outcomes. Patients retained significant medication adherence and daily OFF hours reduction at 12- and 24-weeks follow-up. Conclusion: The results obtained demonstrated that education programs may translate in a notable improvement in motor fluctuations and non-motor symptoms in advanced PD patients.Clinical Trial Registration:Clinicaltrials.gov, identifier NCT04378127.

Study Design and Rationale for Espera Trial: A Multicentre, Randomized, Phase II Clinical Trial Evaluating the Potential Efficacy of Adding SBRT to Pembrolizumab-Pemetrexed Maintenance in Responsive or Stable Advanced Non-Squamous NSCLC After Chemo-Immunotherapy Induction.

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.

Role of ctDNA for the detection of minimal residual disease in resected non-small cell lung cancer: a systematic review.

Background: Operable stage I-III non-small cell lung cancer (NSCLC) has a high risk of recurrence, mainly due to remnant clones of the disease defined as minimal residual disease (MRD). Adjuvant chemotherapy has a limited efficacy in reducing the risk of relapse, and prognostic as well as predictive biomarkers in this context are currently missing. Methods: We performed a systematic review to evaluate the state of the art about the role of circulating tumor DNA detection through liquid biopsy for the assessment of MRD in resected early-stage NSCLC patients. Results: Among the 650 studies identified, 13 were eligible and included. Although highly heterogeneous, all the studies demonstrated a poor prognosis in patients with post-operative MRD, with a detection rate ranging from 6% to 45%. MRD detection preceded radiographic/clinical recurrence by a mean of 5.5 months. MRD positive patients were most likely to benefit from adjuvant treatment in terms of recurrence-free survival (RFS). Consistently, adjuvant therapy did not minimize the risk of relapse in the MRD negative group. Conclusions: Liquid biopsy has a relevant role in assessing post-surgical MRD in resected NSCLC. Since currently there are no criteria other than stage and risk factors for the choice of adjuvant treatment in this setting, post-operative assessment of MRD through liquid biopsy might be a promising approach to guide the decision.

A narrative review on tumor microenvironment in oligometastatic and oligoprogressive non-small cell lung cancer: a lot remains to be done.

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.

Effect of family history, occupation and diet on the risk of Parkinson disease: A case-control study.

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<0.005) starting from the class 65-69 years. Subjects who reported a first degree relative affected by PD showed a borderline increase which was more evident in those enrolled in the urban center of Rome (OR = 1.65; 95%CI: 1.09-2.50). Significant reduction of the risk was associated to current smoking (OR = 0.48; 95%CI: 0.24-0.54), and to vegetables consumption (p<0.03), while borderline increases were associated to meat and cold cut consumption. Occupational activities classified according to ISCO-08 categories did not show increased risk, while higher ORs' were found for pilots and physicians. 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.

Does the Degree of Trunk Bending Predict Patient Disability, Motor Impairment, Falls, and Back Pain in Parkinson's Disease?

Background: Postural abnormalities in Parkinson's disease (PD) form a spectrum of functional trunk misalignment, ranging from a "typical" parkinsonian stooped posture to progressively greater degrees of spine deviation. Objective: To analyze the association between degree of postural abnormalities and disability and to determine cut-off values of trunk bending associated with limitations in activities of daily living (ADLs), motor impairment, falls, and back pain. Methods: The study population was 283 PD patients with ≥5° of forward trunk bending (FTB), lateral trunk bending (LTB) or forward neck bending (FNB). The degrees were calculated using a wall goniometer (WG) and software-based measurements (SBM). Logistic regression models were used to identify the degree of bending associated with moderate/severe limitation in ADLs (Movement Disorders Society Unified PD Rating Scale [MDS-UPDRS] part II ≥17), moderate/severe motor impairment (MDS-UPDRS part III ≥33), history of falls (≥1), and moderate/severe back pain intensity (numeric rating scale ≥4). The optimal cut-off was identified using receiver operating characteristic (ROC) curves. Results: We found significant associations between modified Hoehn & Yahr stage, disease duration, sex, and limitation in ADLs, motor impairment, back pain intensity, and history of falls. Degree of trunk bending was associated only with motor impairment in LTB (odds ratio [OR] 1.12; 95% confidence interval [CI], 1.03-1.22). ROC curves showed that patients with LTB of 10.5° (SBM, AUC 0.626) may have moderate/severe motor impairment. Conclusions: The severity of trunk misalignment does not fully explain limitation in ADLs, motor impairment, falls, and back pain. Multiple factors possibly related to an aggressive PD phenotype may account for disability in PD patients with FTB, LTB, and FNB.

Organisational challenges, volumes of oncological activity and patients' perception during the severe acute respiratory syndrome coronavirus 2 epidemic.

BACKGROUND: On February 23rd, the 1st case of severe acute respiratory syndrome coronavirus 2 (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 bed coronavirus disease (COVID) Unit, and we reshaped our organisation to face the SARS-CoV-2 epidemic, while maintaining oncological activities. METHODS: We tracked down (i) volumes of oncological activities (January 1st - March 31st, 2020 versus the same period of 2019), (ii) patients' and caregivers' perception and (iii) SARS-CoV-2 infection rate in oncology health professionals and SARS-CoV-2 infection-related hospital admissions of "active"' oncological patients. RESULTS: As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations and specialist visits in 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. The overall acceptance of adopted measures, as measured by targeted questionnaires administered to a sample of 241 outpatients, was high (>70%). Overall, 8 of 85 oncology health professionals tested positive for SARS-CoV-2 infection (all but one employed in the COVID Unit, no hospital admissions and no treatment required); among 471 patients admitted for SARS-CoV-2 infection, 7 had an "active"' oncological disease (2 died of infection-related complications). CONCLUSIONS: A slight, but statistically significant reduction in oncology activity was registered during the SARS-CoV-2 epidemic peak in Verona, Italy. Organisational and protective measures adopted appear to have contributed to keep infections in both oncological patients and health professionals to a minimum.

Validity of the wall goniometer as a screening tool to detect postural abnormalities in Parkinson's disease.

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.

Long-term effects of automated mechanical peripheral stimulation on gait patterns of patients with Parkinson's disease.

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).