Beyond Abscopal Effect: A Meta-Analysis of Immune Checkpoint Inhibitors and Radiotherapy in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICI) plus radiotherapy (RT) have been suggested as an emerging combination in non-small cell lung cancer (NSCLC) patients. However, little is known about the magnitude of its benefits and potential clinical predictors. OBJECTIVE: To assess the effects of this combination on the increase in overall and progression-free survival. DATA SOURCES: The MEDLINE and CANCERLIT (1970-2020) electronic databases were searched, and the reference lists of included studies were manually searched. STUDY SELECTION: Studies were included if they were comparative studies between combination ICI-RT and ICI or RT alone in advanced or metastatic NSCLC patients. Overall survival (OS) was analyzed according to the treatment strategy. DATA EXTRACTION: Data on population, intervention, and outcomes were extracted from each study, in accordance with the intention-to-treat method, by two independent observers and combined using the DerSimonian method and Laird method. RESULTS: Compared to ICI or RT alone, ICI-RT significantly increased the 1-year and 3-year OS RR by 0.75 (95% CI 0.64-0.88; p = 0.0003) and 0.85 (95% CI 0.78-0.93; p = 0.0006), respectively. Furthermore, there was a statistically significant benefit on 1- and 3-year progression-free survival (RR 0.73 (95% CI, 0.61-0.87; p = 0.0005) and RR 0.82 (95% CI 0.67-0.99; p = 0.04), respectively). CONCLUSIONS: In patients with advanced or metastatic NSCLC, combination ICI-RT increases 1- and 3-year OS and progression-free survival compared to ICI or RT alone.

Psychological impact of Covid-19 pandemic on oncological patients: A survey in Northern Italy.

The psychological impact of the Covid 19 pandemic on cancer patients, a population at higher risk of fatal consequences if infected, has been only rarely evaluated. This study was conducted at the Departments of Oncology of four hospitals located in the Verona area in Italy to investigate the psychological consequences of the pandemic on cancer patients under active anticancer treatments. A 13-item ad hoc questionnaire to evaluate the psychological status of patients before and during the pandemic was administered to 474 consecutive subjects in the time frame between April 27th and June 7th 2020. Among the 13 questions, 7 were considered appropriate to elaborate an Emotional Vulnerability Index (EVI) that allows to separate the population in two groups (low versus high emotional vulnerability) according to observed median values. During the emergency period, the feeling of high vulnerability was found in 246 patients (53%) and was significantly associated with the following clinical variables: female gender, being under chemotherapy treatment, age ≤ 65 years. Compared to the pre-pandemic phase, the feeling of vulnerability was increased in 41 patients (9%), remained stably high in 196 (42%) and, surprisingly, was reduced in 10 patients (2%). Overall, in a population characterized by an high level of emotional vulnerability the pandemic had a marginal impact and only a small proportion of patients reported an increase of their emotional vulnerability.

Inflammatory indexes as predictive factors for platinum sensitivity and as prognostic factors in recurrent epithelial ovarian cancer patients: a MITO24 retrospective study.

Neutrophil-to-lymphocyte ratio (NLR) and systemic inflammatory index (SII) are prognostic factors in epithelial ovarian cancer (EOC). Their predictive value for platinum-sensitivity and their role in recurrent EOC are unknown. A total of 375 EOC patients were retrospectively analyzed. The correlation between baseline NLR and SII, and platinum-free interval (PFI) according to first line bevacizumab treatment were analyzed using logistic regression analyses adjusted for baseline patient characteristics. Subsequently NLR and SII calculated before second line treatment initiation were evaluated to identify a potential correlation with progression-free survival (PFS) and overall survival (OS) in platinum-sensitive and in platinum-resistant population. In multivariate analysis, NLR ≥ 3 is an independent predictive factor for PFI at 6 months in the chemotherapy group (OR = 2.77, 95% CI 1.38-5.56, p = 0.004), not in bevacizumab treated patients. After having adjusted for ECOG performance status, histology, ascites, bevacizumab treatment at second line and BRCA status, NLR ≥ 3 and SII ≥ 730 are significantly associated with worse OS in platinum-sensitive (HR = 2.69, 95% CI 1.60-4.53, p = 0.002; HR = 2.11, 95% CI 1.29-3.43, p = 0.003, respectively), not in platinum-resistant EOC patients. Low NLR is an independent predictive factor for platinum-sensitivity in patients treated without bevacizumab. NLR and SII are prognostic factors in recurrent platinum-sensitive EOC patients.

Inflammatory Indexes as Prognostic and Predictive Factors in Ovarian Cancer Treated with Chemotherapy Alone or Together with Bevacizumab. A Multicenter, Retrospective Analysis by the MITO Group (MITO 24).

BACKGROUND: The variability in progression-free survival (PFS) and overall survival (OS) among patients with epithelial ovarian cancer (EOC) makes it difficult to reliably predict outcomes. A predictive biomarker of bevacizumab efficacy as first-line therapy in EOC is still lacking. OBJECTIVE: The MITO group conducted a multicenter, retrospective study (MITO 24) to investigate the role of inflammatory indexes as prognostic factors and predictors of treatment efficacy in FIGO stage III-IV EOC patients treated with first-line chemotherapy alone or in combination with bevacizumab. PATIENTS AND METHODS: Of the 375 patients recruited, 301 received chemotherapy alone and 74 received chemotherapy with bevacizumab. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were evaluated to identify a potential correlation with PFS and OS in both the overall population and the two treatment arms. RESULTS: In the overall population, the PFS and OS were significantly longer in patients with low inflammatory indexes (p < 0.0001). In multivariate analyses, the NLR was significantly associated with OS (p = 0.016), and the PLR was significantly associated with PFS (p = 0.024). Inflammatory indexes were significantly correlated with patient prognosis in the chemotherapy-alone group (p < 0.0001). Patients in the chemotherapy with bevacizumab group with a high NLR had a higher PFS and OS (p = 0.026 and p = 0.029, respectively) than those in the chemotherapy-alone group. Conversely, PFS and OS were significantly poorer in patients with a high SII (p = 0.024 and p = 0.017, respectively). CONCLUSION: Our results suggest that bevacizumab improves clinical outcome in patients with a high NLR but may be detrimental in those with a high SII.

In the NadR regulon, adhesins and diverse meningococcal functions are regulated in response to signals in human saliva.

The Neisseria meningitidis regulator NadR was shown to repress expression of the NadA adhesin and play a major role in NadA phase-variable expression. In this study, we identified through microarray analysis over 30 genes coregulated with nadA in the NadR mutant and defined members of the NadR regulon through in vitro DNA-binding assays. Two distinct types of promoter architectures (I and II) were identified for NadR targets, differing in both the number and position of NadR-binding sites. All NadR-regulated genes investigated were found to respond to 4-hydroxyphenylacetic acid (4HPA), a small molecule secreted in human saliva, which was previously demonstrated to induce nadA expression by alleviating NadR-dependent repression. Interestingly, two types of NadR 4HPA responsive activities were found on different NadR targets corresponding to the two types of genes identified by different promoter architectures: while NadA and the majority of NadR targets (type I) are induced, only the MafA adhesins (type II) are corepressed in response to the same 4HPA signal. This alternate behavior of NadR was confirmed in a panel of strains in response to 4HPA and after incubation in saliva. The in vitro NadR binding activity at type I and type II promoter regions is differentially affected by 4HPA, suggesting that the nature of the NadR binding sites may define the regulation to which they will be subjected. We conclude that NadR coordinates a broad transcriptional response to signals present in human saliva, mimicked in vitro by 4HPA, enabling the meningococcus to adapt to the relevant host niche.

A novel epigenetic regulator associated with the hypervirulent Neisseria meningitidis clonal complex 41/44.

Neisseria meningitidis is a major cause of septicemia and meningitis. The hypervirulent clonal complex 41/44 (cc41/44) has emerged as the predominant cause of serogroup B meningococcal disease, having been responsible for recent outbreaks and epidemics worldwide. However, the meningococcal factors that enable transition from asymptomatic carriage to rapidly progressing disease are poorly understood. Here we describe a novel phase-variable DNA methyltransferase, ModD, which was identified in the genome sequence of a New Zealand epidemic isolate. Investigation of the distribution of modD in the wider meningococcal population, by PCR and sequence analysis of genetically diverse N. meningitidis strains, revealed the presence of modD in 20/27 strains in cc41/44, but in only 2/47 strains from other clonal complexes, indicating a significant association of modD with cc41/44 (Fisher's exact P value=3×10(-10)). The modD gene contains 5'-ACCGA-3' repeats that mediate phase variation, leading to reversible on/off switching of modD expression. Microarray analysis of modD-on/off variants revealed that ModD regulates expression of multiple genes involved in colonization, infection, and protection against host defenses, with increased catalase expression in the modD-on variant conferring increased resistance to oxidative stress. The modulation of gene expression via the ModD phase-variable regulon (phasevarion), and its significant association with the cc41/44, suggest a role in the fitness and/or pathogenesis of strains belonging to the cc41/44.

A novel phase variation mechanism in the meningococcus driven by a ligand-responsive repressor and differential spacing of distal promoter elements.

Phase variable expression, mediated by high frequency reversible changes in the length of simple sequence repeats, facilitates adaptation of bacterial populations to changing environments and is frequently important in bacterial virulence. Here we elucidate a novel phase variable mechanism for NadA, an adhesin and invasin of Neisseria meningitidis. The NadR repressor protein binds to operators flanking the phase variable tract and contributes to the differential expression levels of phase variant promoters with different numbers of repeats likely due to different spacing between operators. We show that IHF binds between these operators, and may permit looping of the promoter, allowing interaction of NadR at operators located distally or overlapping the promoter. The 4-hydroxyphenylacetic acid, a metabolite of aromatic amino acid catabolism that is secreted in saliva, induces NadA expression by inhibiting the DNA binding activity of the repressor. When induced, only minor differences are evident between NadR-independent transcription levels of promoter phase variants and are likely due to differential RNA polymerase contacts leading to altered promoter activity. Our results suggest that NadA expression is under both stochastic and tight environmental-sensing regulatory control, both mediated by the NadR repressor, and may be induced during colonization of the oropharynx where it plays a major role in the successful adhesion and invasion of the mucosa. Hence, simple sequence repeats in promoter regions may be a strategy used by host-adapted bacterial pathogens to randomly switch between expression states that may nonetheless still be induced by appropriate niche-specific signals.