Advancing the Care of Pancreatic Cancer Patients: Moving Beyond Just Tumour Tissue
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ABSTRACT:
SUBMITTER: Kalloger S
PROVIDER: S-EPMC8512230 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Advances in recent years have dramatically improved output control by Brain-Machine Interfaces (BMIs). Such devices nevertheless remain robotic and limited in their movements compared to normal human motor performance. Most current BMIs rely on transforming recorded neural activity to a linear state space composed of a set number of fixed degrees of freedom. Here we consider a variety of ways in which BMI design might be advanced further by applying non-linear dynamics observed in normal motor behavior. We consider (i) the dynamic range and precision of natural movements, (ii) differences between cortical activity and actual body movement, (iii) kinematic and muscular synergies, and (iv) the implications of large neuronal populations. We advance the hypothesis that a given population of recorded neurons may transmit more useful information than can be captured by a single, linear model across all movement phases and contexts. We argue that incorporating these various non-linear characteristics will be an important next step in advancing BMIs to more closely match natural motor performance.
| S-EPMC4516874 | biostudies-literature
Project description:BackgroundDecisions regarding whether to administer intensive care to extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients.MethodsWe prospectively studied a cohort of 4446 infants born at 22 to 25 weeks' gestation (determined on the basis of the best obstetrical estimate) in the Neonatal Research Network of the National Institute of Child Health and Human Development to relate risk factors assessable at or before birth to the likelihood of survival, survival without profound neurodevelopmental impairment, and survival without neurodevelopmental impairment at a corrected age of 18 to 22 months.ResultsAmong study infants, 3702 (83%) received intensive care in the form of mechanical ventilation. Among the 4192 study infants (94%) for whom outcomes were determined at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. In multivariable analyses of infants who received intensive care, exposure to antenatal corticosteroids, female sex, singleton birth, and higher birth weight (per each 100-g increment) were each associated with reductions in the risk of death and the risk of death or profound or any neurodevelopmental impairment; these reductions were similar to those associated with a 1-week increase in gestational age. At the same estimated likelihood of a favorable outcome, girls were less likely than boys to receive intensive care. The outcomes for infants who underwent ventilation were better predicted with the use of the above factors than with use of gestational age alone.ConclusionsThe likelihood of a favorable outcome with intensive care can be better estimated by consideration of four factors in addition to gestational age: sex, exposure or nonexposure to antenatal corticosteroids, whether single or multiple birth, and birth weight. (ClinicalTrials.gov numbers, NCT00063063 [ClinicalTrials.gov] and NCT00009633 [ClinicalTrials.gov].).
| S-EPMC2597069 | biostudies-literature
Project description:The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed late so that surgery is rarely curative. Earlier detection could significantly increase the likelihood of successful treatment and improve survival. The aim of the study was to provide proof of principle that point mutations in key cancer genes can be identified by sequencing circulating free DNA (cfDNA) and that this could be used to detect early PDACs and potentially, premalignant lesions, to help target early effective treatment. Targeted next generation sequencing (tNGS) analysis of mutation hotspots in 50 cancer genes was conducted in 26 patients with PDAC, 14 patients with chronic pancreatitis (CP) and 12 healthy controls with KRAS status validated by digital droplet PCR. A higher median level of total cfDNA was observed in patients with PDAC (585 ng/ml) compared to either patients with CP (300 ng/ml) or healthy controls (175 ng/ml). PDAC tissue showed wide mutational heterogeneity, whereas KRAS was the most commonly mutated gene in cfDNA of patients with PDAC and was significantly associated with a poor disease specific survival (p=0.018). This study demonstrates that tNGS of cfDNA is feasible to characterise the circulating genomic profile in PDAC and that driver mutations in KRAS have prognostic value but cannot currently be used to detect early emergence of disease. Importantly, monitoring total cfDNA levels may have utility in individuals "at risk" and warrants further investigation.
| S-EPMC5675628 | biostudies-literature
Project description: Not available
| S-EPMC10569770 | biostudies-literature
Project description:Radiation therapy is a major treatment modality used in > 60% of cancer patients as definitive local treatment for inoperable locoregionally confined tumors and as palliative therapy. Although cytotoxic chemotherapy enhances the effectiveness of treatment, the benefit over radiation therapy alone is modest. There is a need to enhance the effectiveness of local tumor control over what sequentially or concurrently administered cytotoxic chemotherapy provides. Although many biological pathways are known to enhance the effectiveness of radiation therapy, there is currently a paucity of drugs approved for use in combination. Several clinical trials have tested the effectiveness of combining targeted agents or immunotherapies with radiation therapy, but the results of these trials have been negative, likely stemming from the relative lack of preclinical evidence using appropriate experimental standardization or model systems. Accelerating the identification of agents tested in an appropriate clinical context and experimental systems or models would greatly enhance the potential to bring forward early testing of drugs that would not only be safe but also more effective. This article provides an overview of the opportunities and challenges of developing therapeutics to combine with radiation therapy, and some guidance toward preclinical and early clinical testing to improve the chance that advanced phase testing of drug-radiation combinations would be successful in the long term.
| S-EPMC9159468 | biostudies-literature
Project description:Simple Summary Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancers and, disappointingly, neither immune- nor stroma-directed therapies are found to improve upon the current standard of care. Among the most challenging aspects of PDAC biology which impede clinical success are the physiological features of the pancreatic cancer microenvironment (TME), including the presence of a highly fibrotic extracellular matrix marked by perineural invasion and an immunosuppressive milieu. Many current strategies for PDAC therapy are focused on altering these features to improve therapeutic efficacy. This review discusses the recent investigations using organotypic tumor slices as a model system to study cellular and extracellular interactions of the pancreatic TME. Future studies utilizing such models may provide new insights into the TME by identifying mechanisms of communication between multiple cell types and investigating novel therapeutic approaches for personalized cancer therapy. Abstract Organotypic tissue slices prepared from patient tumors are a semi-intact ex vivo preparation that recapitulates many aspects of the tumor microenvironment (TME). While connections to the vasculature and nervous system are severed, the integral functional elements of the tumor remain intact for many days during the slice culture. During this window of time, the slice platforms offer a suite of molecular, biomechanical and functional tools to investigate PDAC biology. In this review, we first briefly discuss the development of pancreatic tissue slices as a model system. Next, we touch upon using slices as an orthogonal approach to study the TME as compared to other established 3D models, such as organoids. Distinct from most other models, the pancreatic slices contain autologous immune and other stromal cells. Taking advantage of the existing immune cells within the slices, we will discuss the breakthrough studies which investigate the immune compartment in the pancreas slices. These studies will provide an important framework for future investigations seeking to exploit or reprogram the TME for cancer therapy.
| S-EPMC8507648 | biostudies-literature
Project description:Pancreatic cancer is the fourth-leading cause of cancer-related deaths worldwide. The outcomes in patients with pancreatic cancer remain unsatisfactory. In the current review, we summarize the genetic and epigenetic architecture of metastatic pancreatic cancer beyond the BRCA mutations, focusing on the genetic alterations and the molecular pathology in pancreatic cancer. This review focuses on the molecular targets for the treatment of pancreatic cancer, with a correlation to future treatments. The potential approach addressed in this review may lead to the identification of a subset of patients with specific biological behaviors and treatment responses.
| S-EPMC9787452 | biostudies-literature
Project description:BackgroundPancreatic cancer exhibits a poor prognosis and often presents with metastasis at diagnosis. Immunotherapeutic approaches targeting private cancer mutations (neoantigens) are a clinically viable option to improve clinical outcomes.Methods3/40 TIL lines (PanTT26, PanTT39, PanTT77) were more closely examined for neoantigen recognition. Whole-exome sequencing was performed to identify non-synonymous somatic mutations. Mutant peptides were synthesised and assessed for antigen-specific IFN-γ production and specific tumour killing in a standard Cr51 assay. TIL phenotype was tested by flow cytometry. Lymphocytes and HLA molecules in tumour tissue were visualised by immunohistochemistry.ResultsPanTT26 and PanTT39 TILs recognised and killed the autologous tumour cells. PanTT26 TIL recognised the KRASG12v mutation, while a PanTT39 CD4+ TIL clone recognised the neoepitope (GLLRYWRTERLF) from an aquaporin 1-like protein (gene: K7N7A8). Repeated stimulation of TILs with the autologous tumour cells line lead to focused recognition of several mutated targets, based on IFN-γ production. TILs and corresponding PBMCs from PanTT77 showed shared as well as mutually exclusively tumour epitope recognition (TIL-responsive or PBMC-responsive).ConclusionThis study provides methods to robustly screen T-cell targets for pancreatic cancer. Pancreatic cancer is immunogenic and immunotherapeutic approaches can be used to develop improved, targeted therapies.
| S-EPMC6325142 | biostudies-literature
Project description:Background and aimsZenker's diverticulum (ZD) is attributed to a poorly compliant cricopharyngeus muscle, and the mainstay of treatment is a cricopharyngeal myotomy. We present a video series summarizing endoscopic treatment options for ZD and related conditions.MethodsWe review the rationale and key technique for various endoscopic treatment modalities for ZD, cricopharyngeal bar, and other esophageal diverticula.ResultsStandard flexible endoscopic cricopharyngeal myotomy involves the division of the common wall or septum of the ZD, aiming for complete transection of the cricopharyngeus. However, recurrence rates are high, likely owing to incomplete myotomy. Zenker's peroral endoscopic myotomy (Z-POEM) uses a proximal submucosal tunnel to provide direct visualization of the cricopharyngeus and septum, allowing confirmation of complete myotomy. We demonstrate an over-the-septum modification to simplify the technique. Submucosal fibrosis, commonly seen in patients with prior treatment, limits submucosal dissection. We present a hybrid technique to overcome this, whereby a traditional septotomy is performed until submucosal tissue is visualized. The intact mucosal flap after Z-POEM in a large ZD may contribute to residual dysphagia. We propose Z-POEM with mucosotomy for large ZD. Finally, we demonstrate modifications for treatment of other esophageal diseases, including cricopharyngeal bar and non-Zenker's esophageal diverticula.ConclusionEndoscopic treatment options for ZD and related conditions are rapidly expanding. With careful tailoring to individual patient characteristics, our expanding arsenal of options allows effective and safe treatment of a broad spectrum of patients.
| S-EPMC8646134 | biostudies-literature
Project description:Resistance to chemotherapy is among the most important issues in the management of ovarian cancer. Unlike cancer cells, which are heterogeneous as a result of remarkable genetic instability, stromal cells are considered relatively homogeneous. Thus, targeting the tumor microenvironment is an attractive approach for cancer therapy. Arguably, anti-vascular endothelial growth factor (anti-VEGF) therapies hold great promise, but their efficacy has been modest, likely owing to redundant and complementary angiogenic pathways. Components of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and other pathways may compensate for VEGF blockade and allow angiogenesis to occur despite anti-VEGF treatment. In addition, hypoxia induced by anti-angiogenesis therapy modifies signaling pathways in tumor and stromal cells, which induces resistance to therapy. Because of tumor cell heterogeneity and angiogenic pathway redundancy, combining cytotoxic and targeted therapies or combining therapies targeting different pathways can potentially overcome resistance. Although targeted therapy is showing promise, much more work is needed to maximize its impact, including the discovery of new targets and identification of individuals most likely to benefit from such therapies.
| S-EPMC4369424 | biostudies-literature