Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in ...significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.
Modern radiotherapy techniques have enabled high focal doses of radiation to be delivered to patients with primary and secondary malignancies of the liver. The current clinical practice of radiation ...oncology has benefitted from decades of research that have informed how to achieve excellent local control and survival outcomes with minimal toxicities. Still, one of the most devastating consequences of radiation to the liver remains a challenge: radiation-induced liver disease (RILD). Here, we will review the current understanding of classic and nonclassic RILD from a clinical perspective, the evaluation and management of patients who are at risk of developing RILD, methods to reduce the likelihood of RILD using modern radiation techniques, and the diagnosis and treatment of radiation-related liver toxicities.
To evaluate the uncertainty of radiomics features from contrast-enhanced breath-hold helical CT scans of non-small cell lung cancer for both manual and semi-automatic segmentation due to ...intra-observer, inter-observer, and inter-software reliability.
Three radiation oncologists manually delineated lung tumors twice from 10 CT scans using two software tools (3D-Slicer and MIM Maestro). Additionally, three observers without formal clinical training were instructed to use two semi-automatic segmentation tools, Lesion Sizing Toolkit (LSTK) and GrowCut, to delineate the same tumor volumes. The accuracy of the semi-automatic contours was assessed by comparison with physician manual contours using Dice similarity coefficients and Hausdorff distances. Eighty-three radiomics features were calculated for each delineated tumor contour. Informative features were identified based on their dynamic range and correlation to other features. Feature reliability was then evaluated using intra-class correlation coefficients (ICC). Feature range was used to evaluate the uncertainty of the segmentation methods.
From the initial set of 83 features, 40 radiomics features were found to be informative, and these 40 features were used in the subsequent analyses. For both intra-observer and inter-observer reliability, LSTK had higher reliability than GrowCut and the two manual segmentation tools. All observers achieved consistently high ICC values when using LSTK, but the ICC value varied greatly for each observer when using GrowCut and the manual segmentation tools. For inter-software reliability, features were not reproducible across the software tools for either manual or semi-automatic segmentation methods. Additionally, no feature category was found to be more reproducible than another feature category. Feature ranges of LSTK contours were smaller than those of manual contours for all features.
Radiomics features extracted from LSTK contours were highly reliable across and among observers. With semi-automatic segmentation tools, observers without formal clinical training were comparable to physicians in evaluating tumor segmentation.
Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The
gene is frequently mutated in pancreatic cancer. In this study, ...we investigated the role of
deficiency in pancreatic cancer cells' response to radiotherapy.
We downregulated SMAD4 expression with
siRNA or
shRNA and overexpressed SMAD4 in
mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of
loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in
-depleted pancreatic cancer cells. Finally, the effects of
on radioresistance were also confirmed in an orthotopic tumor model derived from
-depleted Panc-1 cells.
-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in
-mutant cells rescued their radiosensitivity. Radioresistance mediated by
depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally,
depletion induced
radioresistance in Panc-1-derived orthotopic tumor model (
= 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples.
Our results demonstrate that defective
is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy.
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Cancer treatment efficacy can be significantly enhanced through the elution of drug from nano-carriers that can temporarily stay in the tumor vasculature. Here we present a relatively simple yet ...powerful mathematical model that accounts for both spatial and temporal heterogeneities of drug dosing to help explain, examine, and prove this concept. We find that the delivery of systemic chemotherapy through a certain form of nano-carriers would have enhanced tumor kill by a factor of 2 to 4 over the standard therapy that the patients actually received. We also find that targeting blood volume fraction (a parameter of the model) through vascular normalization can achieve more effective drug delivery and tumor kill. More importantly, this model only requires a limited number of parameters which can all be readily assessed from standard clinical diagnostic measurements (e.g., histopathology and CT). This addresses an important challenge in current translational research and justifies further development of the model towards clinical translation.
Circulating lymphocytes are exquisitely sensitive to radiation exposure, even to low scattered doses which can vary drastically between radiation modalities. We compared the relative risk of ...radiation-induced lymphopenia between intensity modulated radiation therapy (IMRT) or proton beam therapy (PBT) in esophageal cancer (EC) patients undergoing neoadjuvant chemoradiation therapy (nCRT).
EC patients treated with IMRT and PBT were propensity matched based on key clinical variables. Treatment-associated lymphopenia was graded using CTCAE v.4.0. Using matched cohorts, univariate and multivariable multiple logistic regression was used to identify factors associated with increased risk of grade 4 lymphopenia as well as characterize their relative contributions.
Among the 480 patients treated with nCRT, 136 IMRT patients were propensity score matched with 136 PBT patients. In the matched groups, a greater proportion of the IMRT patients (55/136, 40.4%) developed grade 4 lymphopenia during nCRT compared with the PBT patients (24/136, 17.6%, P < 0.0001). On multivariable analysis, PBT was significantly associated with a reduction in grade 4 lymphopenia risk (odds ratio, 0.29; 95% confidence interval, 0.16–0.52; P < 0.0001).
PBT is associated with significant risk reduction in grade 4 lymphopenia during nCRT in esophageal cancer.
For cancer screening to be successful, it should primarily detect cancers with lethal potential or their precursors early, leading to therapy that reduces mortality and morbidity. Screening ...programmes have been successful for colon and cervical cancers, where subsequent surgical removal of precursor lesions has resulted in a reduction in cancer incidence and mortality. However, many types of cancer exhibit a range of heterogeneous behaviours and variable likelihoods of progression and death. Consequently, screening for some cancers may have minimal impact on mortality and may do more harm than good. Since the implementation of screening tests for certain cancers (for example, breast and prostate cancers), a spike in incidence of in situ and early-stage cancers has been observed, but a link to reduction in cancer-specific mortality has not been as clear. It is difficult to determine how many of these mortality reductions are due to screening and how many are due to improved treatments of tumours. In cancers with lower incidence but high mortality (for example, pancreatic cancer), screening has focused on high-risk populations, but challenges similar to those for general population screening remain, particularly with regard to finding lesions with difficult-to-characterize malignant potential (for example, intraductal papillary mucinous neoplasms). More sensitive screening methods are detecting smaller and smaller lesions, but this has not been accompanied by a comparable reduction in the incidence of invasive cancers. In this Opinion article, we focus on the contribution of screening in general and high-risk populations to overdiagnosis, the effects of overdiagnosis on patients and emerging strategies to reduce overdiagnosis of indolent cancers through an understanding of tumour heterogeneity, the biology of how cancers evolve and progress, the molecular and cellular features of early neoplasia and the dynamics of the interactions of early lesions with their surrounding tissue microenvironment.
With increasing use of immunotherapy agents, pretreatment strategies for identifying responders and non-responders is useful for appropriate treatment assignment. We hypothesize that the local immune ...micro-environment of NSCLC is associated with patient outcomes and that these local immune features exhibit distinct radiologic characteristics discernible by quantitative imaging metrics. We assembled two cohorts of NSCLC patients treated with definitive surgical resection and extracted quantitative parameters from pretreatment CT imaging. The excised primary tumors were then quantified for percent tumor PDL1 expression and density of tumor-infiltrating lymphocyte (via CD3 count) utilizing immunohistochemistry and automated cell counting. Associating these pretreatment radiomics parameters with tumor immune parameters, we developed an immune pathology-informed model (IPIM) that separated patients into 4 clusters (designated A-D) utilizing 4 radiomics features. The IPIM designation was significantly associated with overall survival in both training (5 year OS: 61%, 41%, 50%, and 91%, for clusters A-D, respectively, P = 0.04) and validation (5 year OS: 55%, 72%, 75%, and 86%, for clusters A-D, respectively, P = 0.002) cohorts and immune pathology (all P < 0.05). Specifically, we identified a favorable outcome group characterized by low CT intensity and high heterogeneity that exhibited low PDL1 and high CD3 infiltration, suggestive of a favorable immune activated state. We have developed a NSCLC radiomics signature based on the immune micro-environment and patient outcomes. This manuscript demonstrates model creation and validation in independent cohorts.
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic
mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the
...tumor suppressor in nearly 70% of patients. Most
alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between
effectors and mutant p53 remains largely undefined. We show that oncogenic
effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor
, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced
and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic
and mutant p53 to mitigate metastasis. SIGNIFICANCE: Oncogenic
and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic
effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis.
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