The LIPI score and inflammatory biomarkers for selection of patients with solid tumors treated with checkpoint inhibitors.

Over the last decade, immune checkpoint inhibitors (ICI) have completely changed the treatment strategy and the prognosis of several solid cancer types. There is a lack of biomarkers to differ between responders and non-responders to these therapies. The development of biomarkers for immunotherapy has been mainly focused on tumor-related factors. The role of PD-L1 expression or tumor mutational burden (TMB) as potential predictive biomarkers for ICI efficacy is not universal and remains controversial. Moreover, leukocyte and neutrophil counts in blood samples have been used to develop clinical indicators of systemic inflammation like the neutrophil to lymphocyte ratio (NLR) and derived neutrophil to lymphocyte ratio (dNLR) based on the host immunologic status to respond against cancer cells by the immune-effectors. The Lung Immune Prognostic Index (LIPI) score have been developed as a reliable tool to assess the risk stratification of patients with cancer and to guide treatment decisions in the era of personalized cancer treatments. We review the clinical evidence supporting the use of the LIPI index as a clinically valuable biomarker for patients with NSCLC and other solid tumor types, treated with immunotherapy.

Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

BACKGROUND: We aimed to determine whether immune checkpoint inhibitors (ICI) time-of-day infusion might influence the survival of patients with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively analysed patients who received single-agent anti-PD-(L)1 therapy in any line between 2016 and 2021. We calculated by Cox regression models the association between the proportion of ICI infusions received after 16:30h and overall survival (OS) and progression-free survival (PFS). RESULTS: 180 patients were included, 77% received ICI as second- or further-line (median of 12 infusions/patient). The median age was 65 years (IQR 57-70), 112 patients (62%) were male, 165 (92%) were current or former tobacco smokers, 140 (78%) had performance status (PS) 0 or 1, 26 (14%) were on steroid therapy at ICI initiation. Histology was non-squamous for 139 (77%), the median number of metastatic sites was 3, and 33% had brain metastases. Patients who received at least 20% of ICI infusions after 16:30h (65 out of 180, 36%) had a statistically significant shorter median PFS as compared with patients receiving less than 20% of infusions in the evening (4.9 vs 9.4 months, log-rank p = 0.020), while numerical but not statistical shorter OS was observed (14.0 vs 26.2 months, log-rank p = 0.090). In the multivariate analysis, receiving at least 20% of evening infusions did not significantly increase the risk of death, while PS and line of treatment were significantly correlated with the OS. On the contrary, a proportion of ICI administration after 16:30h ≥20% conferred an HR for the PFS of 1.44 (95% CI: 1.01-2.05, p = 0.043), but this prognostic effect was not found when including in the model the total number of ICI infusions received (HR 1.20, 95% CI: 0.83-1.75, p = 0.329). CONCLUSION: Time-of-day infusion of ICI may impact the survival of patients with advanced NSCLC. Underlying prognostic characteristics and the number of infusions received could represent conceivable confounding factors, linked to increased variance related to ICI infusion timing. Nonetheless, further studies may unravel chronobiological mechanisms modulating ICI efficacy.

Consecutive low doses of cyclosporine A induce pro-inflammatory cytokines and accelerate allograft skin rejection.

Cyclosporine A (CsA) is a fungus-derived molecule with potent immunosuppressive activity that has been largely used to downregulate cell-mediated immune responses during transplantation. However, previous data have indicated that CsA shows immunomodulatory activity that relays on the antigen concentration and the dose of CsA used. To test the hypothesis that minimal doses of CsA may show different outcomes on grafts, we used an experimental model for skin transplants in mice. ICR outbred mice received skin allografts and were either treated daily with different doses of CsA or left untreated. Untreated mice showed allograft rejection within 14 days, with graft necrosis, infiltration of neutrophils and macrophages and displayed high percentages of CD8+ T cells in the spleens, which were associated with high serum levels of IL-12, IFN-g and TNF-α. As expected, mice treated with therapeutic doses of CsA (15 mg/kg) did not show allograft rejection within the follow-up period of 30 days and displayed the lowest levels of IL-12, IFN-g and TNF-α as well as a reduction in CD8+ lymphocytes. In contrast, mice treated with consecutive minimal doses of CsA (5×10(-55) mg/kg) displayed an acute graft rejection as early as one to five days after skin allograft; they also displayed necrosis and strong inflammatory infiltration that was associated with high levels of IL-12, IFN-g and TNF-α. Moreover, the CD4+ CD25hiFoxP3+ subpopulation of cells in the spleens of these mice was significantly inhibited compared with animals that received the therapeutic treatment of CsA and those treated with placebo. Our data suggest that consecutive, minimal doses of CsA may affect Treg cells and may stimulate innate immunity.

Cross-sectional area of cervical multifidus muscle in females with chronic bilateral neck pain compared to controls.

DESIGN: Case-control study. OBJECTIVE: To analyze the differences in muscle size and shape of cervical multifidus between patients with bilateral chronic neck pain and healthy subjects. BACKGROUND: Researchers have demonstrated atrophy of lumbar multifidus in patients presenting with low back pain; however, there are only few published reports on cervical multifidus muscle size in individuals with chronic neck pain. METHODS AND MEASURES: Bilateral ultrasound images of multifidus muscle from the third to sixth cervical vertebrae (C3 to C6) were taken in 20 women with bilateral chronic neck pain and 20 healthy women. Cross-sectional area (CSA [cm2]) and muscle shape ratio (ratio between lateral [Lat] and anterior-posterior [AP] dimensions, [Lat/AP]) were measured without knowledge of group assignment. Two separate 3-way (4 x 2 x 2) mixed-model analyses of variance (ANOVAs) with cervical level (C3 to C6) and side (right, left) as within-subject factors and group (patient, control) as the between-subject factor, were used to evaluate differences in CSA and muscle shape ratio between groups, sides, and cervical levels. RESULTS: The ANOVA for CSA indicated a significant effect for cervical level (F = 6.81, P<.001) and group (F = 20.27, P<.001), but not for side (F = 1.26, P = .36). There were no significant interactions among the variables (P>.5). Post hoc analysis showed that the CSA of the C3 multifidus was smaller than the CSA of the C4 (P = .025), C5 (P<.001) or C6 (P<.01) multifidus. There was no significant difference between C4, C5, and C6 multifidus CSA (P>.05). The patients with neck pain had a smaller CSA of the cervical multifidus at all levels compared to controls (P<.001). The ANOVA for muscle shape ratio indicated a significant effect for level (F = 7.84, P<.001) and group (F = 12.501, P<.001), but not for side (F = 0.654, P = .58). There was a significant interaction between level and group (F = 3.651, P = .01). Patients had a wider ovoid shape (greater values in muscle shape ratio) of the C3 (P<.001) and C6 (P<.01) cervical multifidus compared to controls. Further, the C4 multifidus had a smaller shape ratio compared to C6 (P<.001), but was not significantly different than the shape ratio of the C3 and C5 (P>.05) multifidus. CONCLUSIONS: Females with bilateral chronic neck pain had generalized smaller CSA of the cervical multifidus muscles compared to healthy females.