Effectiveness and Safety of Immune Checkpoint Inhibitors for Patients with Advanced Non Small-Cell Lung Cancer in Real-World: Review and Meta-Analysis

Immunotherapy based on anti PD-1/PD-L1 inhibitors is the new standard of advanced non-small cell lung cancers. Pembrolizumab, nivolumab and atezolizumab are used in clinical practice. The strict eligibility criteria of clinical trials do not allow researchers to fully represent treatment effects in the patients that will ultimately use these drugs. We performed a systematic review and a meta-analysis to evaluate the effectiveness and safety of these drugs, and more generally of ICIs, as second-line therapy in NSCLC patients in real world practice. MEDLINE, PubMed, Scopus and Web of Science were searched to include original studies published between January 2015 and April 2020. A total of 32 studies was included in the meta-analysis. The overall radiological response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and overall survival (OS) were 21%, 52%, 3.35 months and 9.98 months, respectively. The results did not change when analysis was adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) and age. A unitary increase in the percent of patients with liver and CNS metastases reduced the occurrence of DCR by 7% (p < 0.001) and the median PFS by 2% (p = 0.010), respectively. The meta-analysis showed that the efficacy and safety of immunotherapy in everyday practice is comparable to that in clinical trials

Lower Tinetti scores can support an early diagnosis of spatial neglect in post-stroke patients

Neglect represents a severe complication of stroke, which impairs patients' daily activities. An early diagnosis of neglect is fundamental for management decisions. The aim of this study is to evaluate the usefulness of the Tinetti Test as an outcome of spatial neglect in post-stroke patients. Observational retrospective data analysis. Rehabilitation Hospital. Cohort of post-stroke adults admitted in our Rehabilitation Unit. One hundred and sixty stroke patients were evaluated between the 1st of January 2015 and the 31st of December 2016 at our Department. Eighty-nine inpatients matched the inclusion criteria. Their scores of the Tinetti Test for balance condition and gait function were compared with Bells Test and line bisection task for spatial neglect. Global independence activity was also assessed using Barthel Index and global cognitive functioning by means of the Mini-Mental State Examination. Twenty-two patients between the 89 patients included in this study were affected by spatial neglect at admission. A high statistical significant correlation was observed between lower Tinetti scores and neglect presence (mean Tinetti Score: 2.36 neglect; 7.82 non-neglect; P<0.001). The Tinetti Test is a well-established assessment scale to measure balance ability and gait function in post-stroke patients. Results from this study suggest that Tinetti Test may be considered as an early ecological screening tool for the diagnosis of neglect in post-stroke patients. The alternative use of the Tinetti Test for the diagnosis of spatial neglect

Antibody Response to COVID-19 mRNA Vaccines in Oncologic and Hematologic Patients Undergoing Chemotherapy

Background: Information on immune responses in cancer patients following mRNA COVID-19 vaccines is still insufficient, but generally, patients had impaired serological responses, especially those with hematological malignancies. We evaluated serological response to COVID-19 mRNA vaccine in cancer patients receiving chemotherapy compared with healthy controls. Methods: In total, 195 cancer patients and 400 randomly selected controls who had been administered a Pfizer-BioNTech or Moderna COVID-19 vaccines in two doses were compared. The threshold of positivity was 4.33 BAU/mL. Patients were receiving anticancer treatment after the first and second dose of the vaccines. Results: a TOTAL OF 169 patients (87%) had solid tumors and 26 hemolymphopoietic diseases. Seropositivity rate was lower in patients than controls (91% vs. 96%), with an age/gender-adjusted rate ratio (RR) of 0.95 (95% CL = 0.89–1.02). Positivity was found in 97% of solid cancers and in 50% of hemolymphopoietic tumors. Both advanced and adjuvant therapy seemed to slightly reduce seropositivity rates in patients when compared to controls (RR = 0.97, 95% CL = 0.89–1.06; RR = 0.94, 95% CL = 0.87–1.01). Conclusions: the response to vaccination is similar in patients affected by solid tumors to controls. On the contrary, hemolymphopietic patients show a much lower response than controls

Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination

<div><p>Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin α2β1γ1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin.</p></div

Model depicting how laminin α2β1γ1 (Lm211) and neuregulin 1 type III (Nrg1III) signaling are integrated during SC development.

<p>In immature SCs, Lm211, via one or more of its basal lamina receptors (Int = integrins, Dystroglycan = Dyst, Gpr126), inhibits protein kinase A (PKA) and prevents Nrg1III from triggering myelination during radial sorting. In promyelinating cells, after radial sorting is finished and the 1:1 relationship with axons larger than 1 μm has been achieved, PKA is activated by Gpr126 independently of Lm211 [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001408#pbio.2001408.ref045" target="_blank">45</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001408#pbio.2001408.ref057" target="_blank">57</a>] and contributes to Nrg1III signaling and to the expression of Oct6. In large myelinating fibers (above), Lm211 inhibition is overcome, PKA is fully active, and cooperates with Nrg1III to activate ErbB2, Grb2-Associated Binder-1 (Gab1), and Egr2. In small myelinated fibers (bottom), Lm211 inhibition of PKA persists and prevents excessive Nrg1III-driven myelination.</p