Introduction: Monitoring the therapeutic response of pancreatic ductal adenocarcinoma (PDAC) patients is crucial to determine treatment strategies. Several studies have examined the effectiveness of ...FOLFIRINOX as a first-line treatment in patients with locally advanced pancreatic cancer, but little attention has been paid to the immunologic alterations in peripheral blood caused by this chemotherapy regimen. Furthermore, the influence of the measurement type (e.g., flow cytometry and targeted gene expression) on the clinical discoveries is unknown. Therefore, we aimed to scrutinize the influence of using flow cytometry or targeted immune gene expression to study the immunological changes in blood samples of PDAC patients who were treated with a single-cycle FOLFIRINOX combined with lipegfilgrastim (FFX-Lipeg). Material and Methods: Whole-blood samples from 44 PDAC patients were collected at two time points: before the first FOLFIRINOX cycle and 14 days after the first cycle. EDTA blood tubes were used for multiplex flow cytometry analyses to quantify 18 immune cell populations and for complete blood count tests as the standard clinical routine. The flow cytometry data were analyzed with FlowJo software. In addition, Tempus blood tubes were used to isolate RNA and measure 1230 immune-related genes using NanoString Technology®. Data quality control, normalization, and analysis were performed using nSolver™ software and the Advanced Analysis module. Results: FFX-Lipeg treatment increased the number of neutrophils and monocytes, as shown by flow cytometry and complete blood count in concordance with elevated gene expression measured via targeted gene expression profiling analysis. Interestingly, flow cytometry analysis showed an increase in the number of B and T cells after treatment, while targeted gene expression analysis showed a decrease in B and T cell-specific gene expression. Conclusions: Targeted gene expression complements flow cytometry analysis to provide a comprehensive understanding of the effects of FFX-Lipeg. Flow cytometry and targeted gene expression showed increases in neutrophils and monocytes after FFX-Lipeg. The number of lymphocytes is increased after treatment; nevertheless, their cell-specific gene expression levels are downregulated. This highlights that different techniques influence clinical discoveries. Therefore, it is important to carefully select the measurement technique used to study the effect of a treatment.
BackgroundThis study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection ...preceded by gemcitabine-based neoadjuvant chemoradiotherapy (nCRT).MethodsPatients originated from the PREOPANC randomised controlled trial. Upfront surgery was performed in 82 patients, and 66 received nCRT before resection. The impact of sex on overall survival (OS) was investigated using Cox proportional hazards models. The immunological landscape within the tumour microenvironment (TME) was mapped using transcriptomic and spatial proteomic profiling.ResultsThe 5-year OS rate differed between the sexes following resection preceded by nCRT, with 43% for women compared with 22% for men. In multivariate analysis, the female sex was a favourable independent prognostic factor for OS only in the nCRT group (HR 0.19; 95% CI 0.07 to 0.52). Multivariate heterogeneous treatment effects analysis revealed a significant interaction between sex and treatment, implying increased nCRT efficacy among women with resected PDAC. The TME of women contained fewer protumoural CD163+MRC1+M2 macrophages than that of men after nCRT, as indicated by transcriptomic and validated using spatial proteomic profiling.ConclusionPDAC tumours of women are more sensitive to gemcitabine-based nCRT, resulting in longer OS after resection compared with men. This may be due to enhanced immunity impeding the infiltration of protumoral M2 macrophages into the TME. Our findings highlight the importance of considering sex disparities and mitigating immunosuppressive macrophage polarisation for personalised PDAC treatment.
Novel prognostic inflammatory markers of cancer survival and cardiovascular disease are; the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the systemic ...immune-inflammation index (SII). As normal values for these markers are unknown, our objective was to obtain reference values in the general population. We obtained data from a population-based prospective cohort study of individuals aged 45 years and over between 2002 and 2014. Absolute blood counts were used to calculate the NLR, PLR and SII. All inflammatory indices followed a log-normal distribution. We calculated the mean and 95% reference intervals in an unselected population. Furthermore we studied whether the inflammatory markers differed between age categories and gender. In total 8,711 participants (57.1% female; mean age 65.9 years, standard deviation 10.5 years) were included. Mean values and corresponding 95% reference intervals for the NLR were: 1.76 (0.83-3.92), for PLR: 120 (61-239) and for SII: 459 (189-1168). The inflammatory markers increased with age. The PLR and SII were higher in females, whilst the NLR was higher in males. In conclusion, we provided reference values for new inflammatory markers. All increase with age and vary with gender. This provides context that allows for proper interpretation of their potential value in future clinical practice and research.
Bronchial and gastroenteropancreatic neuroendocrine tumors (NET) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for ...therapy with Lutetium-177-labeled somatostatin analogues. We have treated over 1,200 patients with peptide receptor radionuclide therapy (PRRT) with
Lu-DOTA
,Tyr
octreotate (
Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival, and toxicity of this therapy.
For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3.7 GBq)
Lu-DOTATATE were included. A subgroup of 443 Dutch patients who were treated with a cumulative dose of at least 600 mCi (22.2 GBq)
Lu-DOTATATE before 2013 was further analyzed for efficacy and survival.
The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months 95% confidence interval (CI), 26-33 months and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). No therapy-related long-term renal or hepatic failure occurred.
PRRT with
Lu-DOTATATE is a favorable therapeutic option in patients with metastatic bronchial and gastroenteropancreatic NETs that express somatostatin receptors. PRRT with
Lu-DOTATATE is safe with few side-effects and shows good response rates with PFS of 29 months and OS of 63 months.
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Several studies found that the systemic immune‐inflammation index (SII) is a prognostic factor for mortality in patients with solid tumors. It is unknown whether an increased SII in generally healthy ...individuals reflects a risk for developing cancer. Our objective was to investigate the association between the SII and incident cancers in a prospective cohort study. Data were obtained from the Rotterdam Study; a population‐based study of individuals aged ≥45 years, between 2002 and 2013. The SII at baseline was calculated from absolute blood counts. The association between the SII and the risk of any solid incident cancer during follow‐up was assessed using Cox proportional hazard models. Individuals with a prior cancer diagnosis were excluded. Data of 8,024 individuals were included in the analyses. The mean age at baseline was 65.6 years (SD 10.5 years) and the majority were women. During a maximum follow‐up period of 10.7 years, 733 individuals were diagnosed with cancer. A higher SII at baseline was associated with a 30% higher risk of developing a solid cancer (HR of 1.30 95% CI; 1.11–1.53), after adjustment for age, sex, socioeconomic status, smoking, BMI and type 2 diabetes. The absolute cumulative 10‐year cancer risk increased from 9.7% in the lowest quartile of SII to 14.7% in the highest quartile (p‐value = 0.009). The risk of developing cancer was persistent over time and increased for individuals with the longest follow‐up. In conclusion, a high SII is a strong and independent risk indicator for developing a solid cancer.
What's new?
The systemic immune‐inflammation index (SII) incorporates blood counts of neutrophils, lymphocytes, and platelets. Several studies have found that the SII can help to predict mortality in patients with solid tumors. Might the SII also be useful in evaluating future cancer risk? In this prospective epidemiologic study, the authors found that an increased SII is independently associated with as much as a 30% higher risk of a future diagnosis of a solid cancer. These results indicate that inflammatory cells could play a role in the etiology of cancer. Further research is needed.
•The FOLFIRINOX inflammatory protein expression profiling (FFX-IPEP) signature effectively identified patients who progressed early during FOLFIRINOX.•The FFX-IPEP liquid biomarker, comprising AMN, ...BANK1, IL1RL2, ITGB6, MYO9B, and PRSS8, surpasses CA19-9 in predicting PDAC progression under FOLFIRINOX.•The FFX-IPEP showed predictive accuracy across all disease stages, removing the need to factor in disease stage for FOLFIRINOX response assessment.•Multi-omics mathematical modeling underscored the predictive accuracy of proteins over genes for PDAC progression under FOLFIRINOX.
Pancreatic ductal adenocarcinoma (PDAC) is often treated with FOLFIRINOX, a chemotherapy associated with high toxicity rates and variable efficacy. Therefore, it is crucial to identify patients at risk of early progression during treatment. This study aims to explore the potential of a multi-omics biomarker for predicting early PDAC progression by employing an in-depth mathematical modeling approach.
Blood samples were collected from 58 PDAC patients undergoing FOLFIRINOX before and after the first cycle. These samples underwent gene (GEP) and inflammatory protein expression profiling (IPEP). We explored the predictive potential of exclusively IPEP through Stepwise (Backward) Multivariate Logistic Regression modeling. Additionally, we integrated GEP and IPEP using Bayesian Kernel Regression modeling, aiming to enhance predictive performance. Ultimately, the FOLFIRINOX IPEP (FFX-IPEP) signature was developed.
Our findings revealed that proteins exhibited superior predictive accuracy than genes. Consequently, the FFX-IPEP signature consisted of six proteins: AMN, BANK1, IL1RL2, ITGB6, MYO9B, and PRSS8. The signature effectively identified patients transitioning from disease control to progression early during FOLFIRINOX, achieving remarkable predictive accuracy with an AUC of 0.89 in an independent test set. Importantly, the FFX-IPEP signature outperformed the conventional CA19-9 tumor marker.
Our six-protein FFX-IPEP signature holds solid potential as a liquid biomarker for the early prediction of PDAC progression during toxic FOLFIRINOX chemotherapy. Further validation in an external cohort is crucial to confirm the utility of the FFX-IPEP signature. Future studies should expand to predict progression under different chemotherapies to enhance the guidance of personalized treatment selection in PDAC.
Preoperative biliary drainage is often performed in patients with obstructive jaundice caused by cancer of the pancreatic head, but the benefit of the procedure is unclear. This randomized trial ...compared 4 to 6 weeks of preoperative biliary drainage, followed by surgery, with immediate surgery alone for cancer of the pancreatic head. The drainage procedure increased morbidity and did not decrease the rate of surgical complications.
This randomized trial compared 4 to 6 weeks of preoperative biliary drainage, followed by surgery, with immediate surgery alone for cancer of the pancreatic head. The drainage procedure increased morbidity and did not decrease the rate of surgical complications.
Obstructive jaundice is the most common symptom in patients with periampullary cancer (located near the ampulla of Vater) or cancer of the pancreatic head. For patients with a resectable tumor who have no radiologic evidence of metastasis, surgical resection is the only option for cure.
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3
Since surgery in patients with jaundice is thought to increase the risk of postoperative complications, preoperative biliary drainage was introduced to improve the postoperative outcome.
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In several experimental studies and retrospective case series, preoperative biliary drainage reduced morbidity and mortality after surgery.
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However, two meta-analyses of randomized trials and a systematic review of . . .
Background Both gastrojejunostomy (GJJ) and stent placement are commonly used palliative treatments of obstructive symptoms caused by malignant gastric outlet obstruction (GOO). Objective Compare GJJ ...and stent placement. Design Multicenter, randomized trial. Setting Twenty-one centers in The Netherlands. Patients Patients with GOO. Interventions GJJ and stent placement. Main Outcome Measurements Outcomes were medical effects, quality of life, and costs. Analysis was by intent to treat. Results Eighteen patients were randomized to GJJ and 21 to stent placement. Food intake improved more rapidly after stent placement than after GJJ (GOO Scoring System score ≥2: median 5 vs 8 days, respectively; P < .01) but long-term relief was better after GJJ, with more patients living more days with a GOO Scoring System score of 2 or more than after stent placement (72 vs 50 days, respectively; P = .05). More major complications (stent: 6 in 4 patients vs GJJ: 0; P = .02), recurrent obstructive symptoms (stent: 8 in 5 patients vs GJJ: 1 in 1 patient; P = .02), and reinterventions (stent: 10 in 7 patients vs GJJ: 2 in 2 patients; P < .01) were observed after stent placement compared with GJJ. When stent obstruction was not regarded as a major complication, no differences in complications were found ( P = .4). There were also no differences in median survival (stent: 56 days vs GJJ: 78 days) and quality of life. Mean total costs of GJJ were higher compared with stent placement ($16,535 vs $11,720, respectively; P = .049 comparing medians). Because of the small study population, only initial hospital costs would have been statistically significant if the Bonferroni correction for multiple testing had been applied. Limitations Relatively small patient population. Conclusions Despite slow initial symptom improvement, GJJ was associated with better long-term results and is therefore the treatment of choice in patients with a life expectancy of 2 months or longer. Because stent placement was associated with better short-term outcomes, this treatment is preferable for patients expected to live less than 2 months. (Clinical trial registration number: ISRCTN 06702358.)
Studies on postoperative complications and survival in patients with pancreatic neuroendocrine tumors (pNET) are sparse and randomized controlled trials are not available. We reviewed all studies on ...postoperative complications and survival after resection of pNET. A systematic search was performed in the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE from 2000–2013. Inclusion criteria were studies of resected pNET, which described postoperative complications separately for each surgical procedure and/or 5-year survival after resection. Prospective and retrospective studies were pooled separately and overall pooled if heterogeneity was below 75 %. The random-effect model was used. Overall, 2643 studies were identified and after full-text analysis 62 studies were included. Pancreatic fistula (PF) rate of the prospective studies after tumor enucleation was 45 %; PF-rates after distal pancreatectomy, pancreatoduodenectomy, or central pancreatectomy were, respectively, 14–14–58 %. Delayed gastric emptying rates were, respectively, 5–5–18–16 %. Postoperative hemorrhage rates were, respectively, 6–1–7–4 %. In-hospital mortality rates were, respectively, 3–4–6–4 %. The 5-year overall survival (OS) and disease-specific survival (DSS) of resected pNET without synchronous resected liver metastases were, respectively, 85–93 %. Heterogeneity between included studies on 5-year OS in patients with synchronous resected liver metastases was too high to pool all studies. The 5-year DSS in patients with liver metastases was 80 %. Morbidity after pancreatic resection for pNET was mainly caused by PF. Liver resection in patients with liver metastases seems to have a positive effect on DSS. To reduce heterogeneity, ISGPS criteria and uniform patient groups should be used in the analysis of postoperative outcome and survival.
Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at advanced stages and associated with early distant metastasis and poor survival. Besides clinical factors, the tumor microenvironment ...(TME) emerged as a crucial determinant of patient survival and therapy response in many tumors, including PDAC. Thus, the presence of tumor-infiltrating lymphocytes and the formation of tertiary lymphoid structures (TLS) is associated with longer survival in PDAC. Although neoadjuvant therapy (NeoTx) has improved the management of locally advanced tumors, detailed insight into its effect on various TME components is limited. While a remodeling towards a proinflammatory state was reported for PDAC-infiltrating T cells, the effect of NeoTx on B cell subsets, including plasma cells, and TLS formation is widely unclear. We thus investigated the frequency, composition, and spatial distribution of PDAC-infiltrating B cells in primary resected (PR) versus neoadjuvant-treated patients using a novel multiplex immunohistochemistry panel. The NeoTx group displayed significantly lower frequencies of pan B cells, GC B cells, plasmablasts, and plasma cells, accompanied by a reduced abundance of TLS. This finding was supported by bulk RNA-sequencing analysis of an independent fresh frozen tissue cohort, which revealed that major B cell pathways were downregulated in the NeoTx group. We further observed that plasma cells frequently formed aggregates that localized close to TLS and that TLS
patients displayed significantly higher plasma cell frequencies compared to TLS
patients in the PR group. Additionally, high densities of CD20
intratumoral B cells were significantly associated with longer overall survival in the PR group. While CD20
B cells held no prognostic value for NeoTx patients, an increased frequency of proliferating CD20
Ki67
B cells emerged as an independent prognostic factor for longer survival in the NeoTx group. These results indicate that NeoTx differentially affects PDAC-infiltrating immune cells and may have detrimental effects on the existing B cell landscape and the formation of TLS. Gaining further insight into the underlying molecular mechanisms is crucial to overcome the intrinsic immunotherapy resistance of PDAC and develop novel strategies to improve the long-term outcome of PDAC patients.
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