Innovate to elevate pancreatic cancer care:Immunity leading the way in precision medicine

Pancreatic cancer is an aggressive malignancy with the lowest 5-year survival rate within the field of oncology, ranking third as a cause of cancer-related death in the United States and Europe. Despite years of dedicated research into treatments for pancreatic cancer, improvements in survival rates have been marginal due to multiple challenges. The foremost factor compromising treatment efficacy is the pancreatic tumor microenvironment (TME), distinguished by its complexity, immunosuppressive nature, and patient heterogeneity. This thesis presents the results of studies aimed at unraveling the immunological landscape of pancreatic cancer and exploring avenues to guide personalized treatment options.Part I of this thesis contains four chapters delving into the immunological and molecular factors impacting the prognosis of patients with resected pancreatic cancer. The goal was to offer valuable insights facilitating the development of tailored and effective immune-based therapies, ultimately elevating patient survival. Part II of this thesis contains five chapters addressing the complexities associated with FOLFIRINOX chemotherapy, a therapeutic pillar in pancreatic cancer. The dilemma surrounding FOLFIRINOX arises due to its toxic nature affecting roughly 70% of patients, coupled with the absence of clinical benefits in 25% of cases. The goal was to examine the multifaced considerations when defining the value of FOLFIRINOX, establish predictive biomarkers for FOLFIRINOX response, and explore the potential synergy of combining immunotherapy with FOLFIRINOX to improve efficacy. Part III of this thesis contains two chapters focusing on rintatolimod, an immune-boosting drug which activates the toll-like receptor 3 (TLR-3), as a potential treatment for advanced pancreatic cancer patients. The goal was to investigate the direct effect of rintatolimod on tumorigenesis in pancreatic cancer cells and, subsequently, the impact of rintatolimod on the peripheral immune landscape.<br/

Schone Handen: als de ene hand de andere wast

Rede, in verkorte vorm uitgesproken ter gelegenheid van het aanvaarden van het ambt van bijzonder hoogleraar met als leeropdracht Chirurgie met specifieke aandacht voor het pancreas, aan het Erasmus MC, faculteit van de Erasmus Universiteit Rotterdam op 25 juni 201

The role of somatostatin receptors in breast and pancreatic cancer

Somatostatin, a hormone which has an inhibitory influence on several physiological processes, is a small peptide consisting of 14 amino-acids, and was first isolated from the hypothalamus of the rat. Soon after, somatostatin was found in numerous other organs, such as the brain, stomach, intestines, pancreas, thyroid, thymus and bronchi, from which it could be extracted. Natural somatostatin has a very short half-life and can only be administered intravenously. The development of several longacting analogues of somatostatin facilitated diagnostic procedures and therapy involving somatostatin and its receptors. One of the first and best known effects of the hormone somatostatin is inhibition of the release of growth hormone by the pituitary gland. Other, mainly inhibitory effects of somatostatin have been described recently, including a direct inhibitory effect on the growth of tumour cells. Somatostatin receptors (SS-R's), present on tumour and pituitary celis, mediate this inhibitory effect as well as release of growth hormone. The analogue octreotide, used in this study, binds to SS-R's on normal and tumour cells. Autoradiography, using '251_ Tyr-octreotide, was utilized to localize receptors for somatostatin in vitro. These receptors were found in several neuroendocrine tumours, as well as in breast carcinomas and islet cell tumours of the pancreas. The aim of this study was to assess the possibility of visualizing SS-R's in vivo, using octreotide labelled with radioactive "'Indium and diethylene-triaminopentaacetic acid (DTPA) as a carrier (octreoscan)

Analyzing Flow Cytometry or Targeted Gene Expression Data Influences Clinical Discoveries—Profiling Blood Samples of Pancreatic Ductal Adenocarcinoma Patients

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.</p

FOLFIRINOX chemotherapy modulates the peripheral immune landscape in pancreatic cancer:Implications for combination therapies and early response prediction

Background: FOLFIRINOX chemotherapy has improved outcomes for pancreatic cancer patients, but poor long-term survival outcomes and high toxicity remain challenges. This study investigates the impact of FOLFIRINOX on plasma proteins and peripheral immune cells to guide immune-based combination therapies and, ideally, to identify a potential biomarker to predict early disease progression during FOLFIRINOX. Methods: Blood samples were collected from 86 pancreatic cancer patients before and two weeks after the first FOLFIRINOX cycle and subjected to comprehensive immune cell and proteome profiling. Principal Component Analysis and Linear Mixed Effect Regression models were used for data analysis. FOLFIRINOX efficacy was radiologically evaluated after the fourth cycle. Results: One cycle of FOLFIRINOX diminished tumour-cell-related pathways and enhanced pathways related to immune activation, illustrated by an increase in pro-inflammatory IL–18, IL–15, and TNFRSF4. Similarly, FOLFIRINOX promoted the activation of CD4 + and CD8 + T cells, the proliferation of NK(T), and the activation of antigen-presenting cells. Furthermore, high pre-treatment levels of VEGFA and PRDX3 and an elevation in FCRL3 levels after one cycle predicted early progression under FOLFIRINOX. Finally, patients with progressive disease exhibited high levels of inhibitory markers on B cells and CD8 + T cells, while responding patients exhibited high levels of activation markers on CD4 + and CD8 + T cell subsets. Conclusion: FOLFIRINOX has immunomodulatory effects, providing a foundation for clinical trials exploring immune-based combination therapies that harness the immune system to treat pancreatic cancer. In addition, several plasma proteins hold potential as circulating predictive biomarkers for early prediction of FOLFIRINOX response in patients with pancreatic cancer.</p

Functional changes after pancreatoduodenectomy: Diagnosis and treatment

Relatively little is known about the gastrointestinal function after recovery of a pancreatoduodenectomy. This review focuses on the functional changes of the stomach, duodenum and pancreas that occur after pancreatoduodenectomy. Although the mortality in relation to pancreatoduodenectomy has decreased over the years, it remains associated with considerable morbidity, which occurs in 40-60% of patients. Physical complaints early after the operation are often caused by motility disorders, in particular delayed gastric emptying, which occurs in up to 40% of patients. During longer follow-up of these patients the occurrence of endocrine and exocrine pancreatic insufficiency becomes more predominant. Diabetes mellitus develops in 20-50% of patients after a pancreatic resection (pancreatogenic diabetes). The main presenting symptoms of exocrine insufficiency are weight loss and steatorrhea. Its presence is suspected on clinical ground and can be supported by fecal elastase-1 measurement. Exocrine insufficiency can be compensated with oral enteric-coated enzyme supplements. The quality of life issue will be addressed as an important outcome measurement after pancreaticoduodenectomy. Furthermore, the functional changes after pancreatoduodenectomy are described in detail with suggestions for diagnosis and treatment

Mammographic and sonographic spectrum of non-puerperal mastitis

The goal of this study was to explore possible specific mammographic and sonographic features in women with non-puerperal mastitis (NPM), in order to make an accurate diagnosis and prevent unnecessary surgical procedures. From a group of 93 patients with NPM diagnosed between 1987 and 1992, the mammograms of 41, the sonograms and cytology of 47, and the histology of seven patients were retrospectively reviewed. Follow-up was performed on those without histology. In 20 of the 47 patients the inflammation was located subareolarly. In 50% of those with non-subareolar lesions, mammography showed a circumscribed lesion. Sonographically, all patients had an identifiable lesion either well or poorly defined. The majority of the lesions were cystic, but in 23 of 47 cases solid components were seen. Signs of infection in cystic lesions were observed in 25 of 47 cases. Posterior shadowing was not observed. During the follow-up period no breast malignancy was found. It is concluded that NPM has no specific mammographic or sonographic sign. Diagnosis should be made with additional diagnostic assessment, such as FNAB, which was diagnostic in all cases