The role of brain radiotherapy for EGFR- and ALK-positive non-small-cell lung cancer with brain metastases: a review.

Non-small cell lung cancer (NSCLC) is frequently complicated by central nervous system (CNS) metastases affecting patients' life expectancy and quality. At the present clinical trials including neurosurgery, radiotherapy (RT) and systemic treatments alone or in combination have provided controversial results. CNS involvement is even more frequent in NSCLC patients with EGFR activating mutations or ALK rearrangement suggesting a role of target therapy in the upfront treatment in place of loco-regionals treatments (i.e. RT and/or surgery). So far clinical research has not explored the potential role of accurate brain imaging (i.e. MRI instead of the routine total-body contrast CT and/or PET/CT staging) to identify patients that could benefit of local therapies. Moreover, for patients who require concomitant RT there are no clear guidelines on the timing of intervention with respect to innovative precision medicine approaches with Tyrosine Kinase Inhibitors, ALK-inhibitors and/or immuno-oncological therapies. On this basis the present review describes the therapeutic strategies integrating medical and radiation oncology in patients with metastatic NSCLC (mNSCLC) adenocarcinoma with CNS involvement and EGFR activating mutations or ALK rearrangement.

PD-1/PD-L1 immune-checkpoint blockade induces immune effector cell modulation in metastatic non-small cell lung cancer patients: A single-cell flow cytometry approach.

Peripheral immune-checkpoint blockade with mAbs to programmed cell death receptor-1 (PD-1) (either nivolumab or pembrolizumab) or PD-Ligand-1 (PD-L1) (atezolizumab, durvalumab, or avelumab) alone or in combination with doublet chemotherapy represents an expanding treatment strategy for metastatic non-small cell lung cancer (mNSCLC) patients. This strategy lays on the capability of these mAbs to rescue tumor-specific cytotoxic T lymphocytes (CTLs) inactivated throughout PD-1 binding to PD-L1/2 in the tumor sites. This inhibitory interactive pathway is a physiological mechanism of prevention against dangerous overreactions and autoimmunity in case of prolonged and/or repeated CTL response to the same antigen peptides. Therefore, we have carried out a retrospective bioinformatics analysis by single-cell flow cytometry to evaluate if PD-1/PD-L1-blocking mAbs modulate the expression of specific peripheral immune cell subsets, potentially correlated with autoimmunity triggering in 28 mNSCLC patients. We recorded a treatment-related decline in CD4+ T-cell and B-cell subsets and in the neutrophil-to-lymphocyte ratio coupled with an increase in natural killer T (NKT), CD8+PD1+ T cells, and eosinophils. Treatment-related increase in autoantibodies [mainly antinuclear antibodies (ANAs) and extractable nuclear antigen (ENA) antibodies] as well as the frequency of immune-related adverse events were associated with the deregulation of specific immune subpopulations (e.g., NKT cells). Correlative biological/clinical studies with deep immune monitoring are badly needed for a better characterization of the effects produced by PD-1/PD-L1 immune-checkpoint blockade.

Efficacy and Effect of Inhaled Adenosine Treatment in Hospitalized COVID-19 Patients.

Lack of specific antiviral treatment for COVID-19 has resulted in long hospitalizations and high mortality rate. By harnessing the regulatory effects of adenosine on inflammatory mediators, we have instituted a new therapeutic treatment with inhaled adenosine in COVID-19 patients, with the aim of reducing inflammation, the onset of cytokine storm, and therefore to improve prognosis. The use of inhaled adenosine in COVID19 patients has allowed reduction of length of stay, on average 6 days. This result is strengthened by the decrease in SARS-CoV-2 positive days. In treated patients compared to control, a clear improvement in PaO2/FiO2 was observed together with a reduction in inflammation parameters, such as the decrease of CRP level. Furthermore, the efficacy of inhaled exogenous adenosine led to an improvement of the prognosis indices, NLR and PLR. The treatment seems to be safe and modulates the immune system, allowing an effective response against the viral infection progression, reducing length of stay and inflammation parameters.

Therapeutic effects of adenosine in high flow 21% oxygen aereosol in patients with Covid19-pneumonia.

BACKGROUND: SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine→A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage. The treatment was allowed, considering that adenosine has several clinical applications. PATIENTS AND TREATMENT: Fourteen consecutively enrolled patients with Covid19-related interstitial pneumonitis and PaO2/FiO2 ratio<300 received off-label-treatment with 9 mg inhaled adenosine every 12 hours in the first 24 hours and subsequently, every 24 days for the next 4 days. Fifty-two patients with analogue features and hospitalized between February and April 2020, who did not receive adenosine, were considered as a historical control group. Patients monitoring also included hemodynamic/hematochemical studies, CTscans, and SARS-CoV2-tests. RESULTS: The treatment was well tolerated with no hemodynamic change and one case of moderate bronchospasm. A significant increase (> 30%) in the PaO2/FiO2-ratio was reported in 13 out of 14 patients treated with adenosine compared with that observed in 7 out of52 patients in the control within 15 days. Additionally, we recorded a mean PaO2/FiO2-ratio increase (215 ± 45 vs. 464 ± 136, P = 0.0002) in patients receiving adenosine and no change in the control group (210±75 vs. 250±85 at 120 hours, P>0.05). A radiological response was demonstrated in 7 patients who received adenosine, while SARS-CoV-2 RNA load rapidly decreased in 13 cases within 7 days while no changes were recorded in the control group within 15 days. There was one Covid-19 related death in the experimental group and 11in the control group. CONCLUSION: Our short-term analysis suggests the overall safety and beneficial therapeutic effect of inhaled adenosine in patients with Covid-19-inflammatory lung disease suggesting further investigation in controlled clinical trials.

GOLFIG Chemo-Immunotherapy in Metastatic Colorectal Cancer Patients. A Critical Review on a Long-Lasting Follow-Up.

Background: GOLFIG is a chemo-immunotherapy regimen established in preclinical models that combines gemcitabine + FOLFOX (fluoropyrimidine backbone coupled to oxaliplatin) poly-chemotherapy with low-dose s. c. recombinant interleukin-2 (rIL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF). Promising antitumor effects in metastatic colorectal cancer (mCRC) patients were obtained in previous phase II and III trials. Here we report the results of 15 years of follow-up. Methods: This is a multi-institutional retrospective analysis including 179 mCRC patients receiving GOLFIG regimen between June 2002 and June 2018. Sixty-two of them received the treatment as frontline (enrolled in the GOLFIG-2 phase III trial) and 117 as second/third line (49 enrolled in the GOLFIG-1 phase II trial and 68 as compassionate use). One hundred twelve patients showed a primary left side and 67 a primary right side; K/N-ras mutational status was available in 74 cases, and an activating mutation was detected in 33. Kaplan-Meier and Cox regression analyses were carried out to relate PFS and OS with different parameters. Results: Overall, we recorded a mean PFS and OS of 15.28 (95% CI: 10.36-20.20) and 24.6 (95% CI: 19.07-30.14) months, respectively, with 14 patients surviving free of progression for 10 years. This regimen, in our updated survey of the GOLFIG-2 trial, confirmed superiority over FOLFOX in terms of PFS (hazard ratio (HR) = 0.58, p = 0.006) with a trend to a longer OS (HR = 0.69, P = 0.06) in the first line. Our analysis also confirmed significant antitumor activity in pre-treated patients, reporting a mean PFS and OS of 12.55 (95% CI: 7.19-17.9) and 20.28 (95% CI: 14.4-26.13) months, respectively. Immune-related adverse events (irAEs) were recorded in 24% of the cases and were related to a longer survival (HR = 0.36; P = 0.0001). Finally, patients' outcome was not correlated to sex, sidedness, and MT-K/N-ras. Conclusions: The GOLFIG regimen is a reliable underestimated therapeutic option in pre-treated mCRC patients and offers a strong rationale to design further trials.