Pancreatic ductal adenocarcinoma (PDAC) is a non-immunogenic tumor poorly responsive to immune checkpoint inhibitors. This study investigates the effect of 5-fluorouracil (5-FU), irinotecan, and ...oxaliplatin (FOLFIRINOX), and gemcitabine plus nab-paclitaxel (GEMnPAC) regimens on PD-L1 mRNA expression in plasma-derived microvesicles (MVs) in 50 PDAC patients. Plasma was collected before starting chemotherapy and after 3 months of treatment. mRNA was extracted from MVs, and PD-L1 expression was measured by digital droplet PCR. Twenty-eight patients were PD-L1 positive in MVs at baseline, of which 18 were in the GEMnPAC cohort and 10 in the FOLFIRINOX one. The amount of PD-L1 expression in MVs increased from baseline to 3 months of treatment in patients receiving GEMnPAC (median value 0.002 vs. 0.005;
= 0.01) compared to those treated with FOLFIRINOX (median 0.003 vs. 0.004;
= 0.97). The increase in PD-L1 mRNA expression in MVs was not related to tumor response (PR + SD:
= 0.08; PD:
= 0.28). Our findings demonstrate that GEMnPAC can increase PD-L1 mRNA expression in patient-derived circulating MVs, providing a rationale for testing the efficacy of this regimen in sequential or simultaneous combinations with immunotherapy in PDAC patients.
Alzheimer's disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of ...homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the
homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (
= 9) or no carriers (
= 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1β, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFβ), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression.
The Italian National Institute of Health (Istituto Superiore di Sanità) funded a 30-month project (July 2021-January 2024) to conduct a twin study of the relationships between Positive Mental Health ...(PMH) and cellular longevity. Only a few previous studies have focused on the biomarkers of aging in relation to psychological well-being, and none of them exploited the potential of the twin design.
In this project, following the standard procedures of the Italian Twin Registry (ITR), we aim to recruit 200 adult twin pairs enrolled in the ITR. They are requested to complete a self-report questionnaire battery on PMH and to undergo a blood withdrawal for the assessment of aging biomarkers, i.e., telomere length and mitochondrial DNA functionality. The association between psychological and aging biomarker measures will be assessed, controlling for genetic and familial confounding effects using the twin study design.
Biomarker assays are underway. Once data are available for the total study sample, statistical analyses will be performed. The project's results may shed light on new mechanisms underlying the mind-body connection and may prove helpful to promote psychological well-being in conjunction with biological functioning.
Background
Inflammation is a long-established hallmark of liver fibrosis and carcinogenesis. Eosinophils are emerging as crucial components of the inflammatory process influencing cancer development. ...The role of blood eosinophils in patients with hepatocellular carcinoma receiving systemic treatment is an unexplored field.
Objective
The objective of this study was to analyse the prognostic role of the baseline eosinophil count in patients with sorafenib-treated hepatocellular carcinoma.
Patients and Methods
A training cohort of 92 patients with advanced- or intermediate-stage sorafenib-treated hepatocellular carcinoma and two validation cohorts of 65 and 180 patients were analysed. Overall survival and progression-free survival in relation to baseline eosinophil counts were estimated by the Kaplan–Meier method. Univariate and multivariate analyses were performed.
Results
A negative prognostic impact of low baseline eosinophil counts (< 50*10
9
/L) was demonstrated in all cohorts (training cohort: hazard ratio = 50.1, 95% confidence interval 11.6–216.5,
p
< 0.0001 for low vs high eosinophil counts; first validation cohort: hazard ratio = 4.55, 95% confidence interval 1.24–16.65,
p
= 0.022; second validation cohort: hazard ratio = 3.21, 95% confidence interval 1.83–5.64,
p
< 0.0001). Moreover, low eosinophil counts had a negative prognostic role in patients progressing on or intolerant to sorafenib who received second-line regorafenib, but not capecitabine or best supportive care.
Conclusions
Our analysis identified baseline blood eosinophil counts as a new prognostic factor in patients with sorafenib-treated hepatocellular carcinoma. Concerning second-line therapies, eosinophil counts were associated with survival outcomes only in regorafenib-treated patients, suggesting a possible predictive role in this setting.
Aim
A link has been established between malnutrition, immunological status, and hepatocellular carcinoma (HCC). The prognostic nutritional index (PNI) has been recognized as a prognostic indicator in ...early‐stage HCC and in patients treated with first‐line therapy. However, to date, the role of the PNI in HCC patients treated with regorafenib has not been reported.
Methods
We undertook a multicentric analysis on a cohort of 284 patients affected by advanced HCC treated with regorafenib. The PNI was calculated as follows: 10 × serum albumin concentration (g/dl) + 0.005 × peripheral lymphocyte count (number/mm3). Univariate and multivariate analyses were used to investigate the association between PNI and survival outcomes.
Results
A PNI cut‐off value of 44.45 was calculated by a receiver operating characteristic analysis. The median overall survival was 12.8 and 7.8 months for patients with high (>44.45) and low (≤44.45) PNI, respectively (hazard ratio, 0.58; 95% confidence interval, 0.43–0.77; p = 0.0002). In the univariate and multivariate analyses, low PNI value and increased serum bilirubin level emerged as independent prognostic factors for overall survival. No differences were found between high and low PNI in terms of progression‐free survival (p = 0.14).
Conclusion
If validated, the PNI could represent an easy‐to‐use prognostic tool able to guide the clinical decision‐making process in HCC patients treated with regorafenib.
Background
The results of the pivotal RESORCE trial led to the approval of the tyrosine kinase inhibitor regorafenib as second-line treatment in advanced hepatocellular carcinoma (HCC) after ...sorafenib failure. Data about prognostic factors in a second-line HCC setting are scarce.
Objective
The aim of the present study was to investigate prognostic factors in a cohort of patients with advanced HCC treated with regorafenib after progressing on sorafenib.
Methods
We retrieved the data of 259 patients affected by advanced HCC treated with regorafenib as second-line treatment from four different Italian institutions and one South Korean institution and performed a recursive partitioning analysis to build a score system.
Results
At the first-step univariate analysis for overall survival (OS), alkaline phosphatase (ALP) was the most significant parameter and was chosen as the first node in our tree model. In the subpopulation of patients presenting with ALP ≤122 U/L (n=155) at baseline, the most statistically significant split was by progression-free survival (PFS) on previous sorafenib treatment, between patients with a PFS ≥ 6 months (
n
= 59) and patients with a PFS < 6 months (
n
= 96). In the subpopulation of patients with ALP ≤ 122 U/L and PFS to sorafenib ≥ 6 months, the final split was determined between patients with hepatitis B virus (HBV)-related liver disease (
n
= 22) and patients with no HBV-related liver disease (
n
= 37). In the subpopulation of patients presenting ALP >122 U/L (
n
= 104) at baseline, the most statistically significant split was by aspartate aminotransferase (AST) value, between patients with AST ≤ 56 U/L (
n
= 48) and patients with AST > 56 U/L (
n
= 56). We built the Regorafenib Prognostic Index (REP index) stratifying the population into “low-risk,” “medium-risk,” and “high-risk” groups. The difference in median OS between the three risk groups was statistically significant, being 20.8 months (95% confidence interval CI 10.0–46.3) in the “low-risk” group, 8.4 months (95% CI 7.2–1435.8) in the “medium-risk” group, and 5.5 months (95% CI 3.5–13.2) in the “high risk” group. The median PFS was 7.7 months (95% CI 3.7–19.3), 2.5 months (95% CI 2.1–28.8), and 2.4 months (95% CI 1.6–9.1) for the “low-risk,” “medium-risk,” and “high-risk” groups, respectively.
Conclusion
The REP index is an independent prognostic factor for OS and PFS in patients with advanced HCC treated with regorafenib.
Sarcopenia is recognised as a predictor of toxicity and survival in localised and locally advanced gastric cancer (GC). Its prognostication power in advanced unresectable or metastatic GC (aGC) is ...debated. The survival impact of visceral and subcutaneous fat distribution (visceral fat area (VFA)/subcutaneous fat area (SFA)) is ambiguous. Our aim was to determine the influence of body composition parameters (BCp) on toxicity and survival in aGC patients undergoing palliative treatment. BCp were retrospectively assessed by baseline computed tomography for 78 aGC patients who received first-line chemotherapy from March 2010 to January 2017. Correlations between BCp and toxicity and survival were calculated by χ
-test and by log-rank-test and Cox-model, respectively. Sarcopenia fails to show association with progression-free survival (PFS) (
= 0.44) and overall survival (OS) (
= 0.88). However, sarcopenia influences the development of high-grade neutropenia (
= 0.048) and mucositis (
= 0.054). VFA/SFA (high vs. all the rest) results as a strong predictor of objective response (
= 0.02) and outcome (PFS,
= 0.001; OS,
= 0.02). At multivariate analysis for PFS, prognostic factors are VFA/SFA (
= 0.03) and a neutrophil-lymphocyte ratio >3. The same factors remain significant for OS (each
= 0.03) along with Eastern Cooperative Oncology Group (ECOG) performance status (
= 0.008) and number of metastatic sites ≥2 (
< 0.001). In our cohort of aGC, VFA/SFA exhibit a robust impact on survival, with a higher sensitivity than sarcopenia.
Early tumor shrinkage (ETS) and depth of response (DoR) predict favorable outcomes in metastatic colorectal cancer. We aim to evaluate their prognostic role in metastatic pancreatic cancer (PC) ...patients treated with first-line modified-FOLFIRINOX (FOLFOXIRI) or Gemcitabine + Nab-paclitaxel (GemNab). Hence, 138 patients were tested for ETS, defined as a ≥20% reduction in the sum of target lesions' longest diameters (SLD) after 6-8 weeks from baseline, and DoR, i.e., the maximum percentage shrinkage in the SLD from baseline. Association of ETS and DoR with progression-free survival (PFS) and overall survival (OS) was assessed. ETS was reached in 49 patients (39.5% in the FOLFOXIRI, 29.8% in the GemNab group;
= 0.280). In the overall population, ETS was significantly associated with better PFS (8.0 vs. 4.8 months,
< 0.001) and OS (13.2 vs. 9.7 months,
= 0.001). Median DoR was -27.5% (-29.4% with FOLFOXIRI and -21.4% with GemNab,
= 0.016): DoR was significantly associated with better PFS (9.0 vs. 6.7 months,
< 0.001) and OS (14.3 vs. 11.1 months,
= 0.031). Multivariate analysis confirmed both ETS and DoR are independently associated with PFS and OS. In conclusion, our study added evidence on the role of ETS and DoR in the prediction of outcome of PC patients treated with first-line combination chemotherapy.
An Online First version of this article was made available online at
https://link.springer.com/article/10.1007/s11523-020-00757-3
on 12 October 2020. Errors were subsequently identified in the ...article, and the following corrections should be noted.
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