Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a ...challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation.
We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts.
We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue).
We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells.
ArrayExpress accession number: E-MTAB-6134.
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Whereas most PPGLs are benign, up to 20% may become metastatic with
- and
-mutated tumors showing the higher risk. We ...aimed at determining the contribution of immortalization mechanisms to metastatic progression.
Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (+) tumors, we analyzed genomic alterations leading to transcriptional activation of
comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and
mutations by next-generation sequencing. Univariate/multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes.
Only 37 of 200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors and was prevalent in
-mutated paragangliomas (
= 2.42e-09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group (
= 0.169), yet
mutations were found preferentially in
-mutated metastatic tumors (
= 0.0014). Telomerase activation and
mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1;
= 6.50E-07 and 1.90E-07, respectively); OS (hazard ratio, 97.4 and 44.1;
= 4.30E-03 and 2.00E-03, respectively) and were associated with worse MFS and OS (log-rank tests
< 0.0001).
Assessment of telomerase activation and
mutations could be used to identify metastatic PPGLs, particularly in tumors at high risk of progression.
Although pancreatic precancerous lesions are known to be related to obesity and fatty pancreatic infiltration, the mechanisms remain unclear. We assessed the role of fatty infiltration in the process ...of pancreatic oncogenesis and obesity. A combined transcriptomic, lipidomic and pathological approach was used to explore neoplastic transformations. Intralobular (ILF) and extralobular (ELF) lipidomic profiles were analyzed to search for lipids associated with pancreatic intraepithelial neoplasia (PanINs) and obesity; the effect of ILF and ELF on acinar tissue and the histopathological aspects of pancreatic parenchyma changes in obese (OB) and non-obese patients. This study showed that the lipid composition of ILF was different from that of ELF. ILF was related to obesity and ELF-specific lipids were correlated to PanINs. Acinar cells were shown to have different phenotypes depending on the presence and proximity to ILF in OB patients. Several lipid metabolic pathways, oxidative stress and inflammatory pathways were upregulated in acinar tissue during ILF infiltration in OB patients. Early acinar transformations, called acinar nodules (AN) were linked to obesity but not ELF or ILF suggesting that they are the first reversible precancerous pancreatic lesions to occur in OB patients. On the other hand, the number of PanINs was higher in OB patients and was positively correlated to ILF and ELF scores as well as to fibrosis. Our study suggests that two types of fat infiltration must be distinguished, ELF and ILF. ILF plays a major role in acinar modifications and the development of precancerous lesions associated with obesity, while ELF may play a role in the progression of PDAC.
This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma.
Eligible ...patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population.
141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1–8.8) in the eryaspase arm versus 4.9 months (3.1–7.1) in the control arm (HR, 0.63; 95% CI, 0.39–1.01; P = 0.056) and 2.0 months (95% CI, 1.8–3.4) in the eryaspase arm versus 1.8 months (1.4–3.8) in the control arm (HR, 0.67; 95% CI, 0.40–1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37–0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 17.2%), neutropenia (12 12.9%), and physical health deterioration (12 12.9%).
Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.
•Eryaspase provides encapsulated asparaginase within erythrocytes to minimize toxicity.•Asparagine synthetase (ASNS) appears to be a prognostic indicator of pancreatic cancer.•Eryaspase plus chemotherapy improved patient survival, irrespective of ASNS expression.
Mortality from pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide and effective new treatments are urgently needed. The current treatment of metastatic PDAC in fit patients is based on ...two chemotherapy combinations (FOLFIRINOX and gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all treatments targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results were observed in the small subpopulations of patients with germline BRCA 1/2 mutations, and somatic gene fusions (neurotrophic tyrosine receptor kinase, Neuregulin 1, which are enriched in KRAS wild-type PDAC), KRAS G12C mutations, or microsatellite instability. While targeted tumor metabolism therapies and immunotherapy have been disappointing, they are still under investigation in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are other promising avenues of research. This review evaluates the current expectations and limits of available treatments and analyses the existing trials. A permanent search for actionable vulnerabilities in PDAC tumor cells and microenvironments will probably result in a more personalized therapeutic approach, keeping in mind that supportive care must also play a major role if real clinical efficacy is to be achieved in these patients.
To assess the performance of CT-based radiomics analysis in differentiating benign from malignant intraductal papillary mucinous neoplasms of the pancreas (IPMN), preoperative scans of 408 resected ...patients with IPMN were retrospectively analyzed. IPMNs were classified as benign (low-grade dysplasia, n = 181), or malignant (high grade, n = 128, and invasive, n = 99). Clinicobiological data were reported. Patients were divided into a training cohort (TC) of 296 patients and an external validation cohort (EVC) of 112 patients. After semi-automatic tumor segmentation, PyRadiomics was used to extract radiomics features. A multivariate model was developed using a logistic regression approach. In the training cohort, 85/107 radiomics features were significantly different between patients with benign and malignant IPMNs. Unsupervised clustering analysis revealed four distinct clusters of patients with similar radiomics features patterns with malignancy as the most significant association. The multivariate model differentiated benign from malignant tumors in TC with an area under the ROC curve (AUC) of 0.84, sensitivity (Se) of 0.82, specificity (Spe) of 0.74, and in EVC with an AUC of 0.71, Se of 0.69, Spe of 0.57. This large study confirms the high diagnostic performance of preoperative CT-based radiomics analysis to differentiate between benign from malignant IPMNs.
General anesthesia for breast surgery may be supplemented by using a regional anesthetic technique. We evaluated the efficacy of the first pectoral nerve block (Pecs I) in treating postoperative pain ...after breast cancer surgery.
A randomized, double-blind, dual-centered, placebo-controlled trial was performed. One hundred twenty-eight patients scheduled for unilateral breast cancer surgery were recruited. A multimodal analgesic regimen and surgeon-administered local anesthetic infiltration were used for all patients. Ultrasound-guided Pecs I was performed using bupivacaine or saline. The primary outcome was the patient pain score (numerical rating scale NRS) in the recovery unit 30 minutes after admission or just before the morphine administration (NRS ≥4/10). The secondary outcomes were postoperative opioid consumption (ie, in the recovery unit and after 24 hours).
During recovery, no significant difference in NRS was observed between the bupivacaine (n = 62, 3.0 1.0-4.0) and placebo (n = 65, 3.0 1.0-5.0) groups (P = 0.55). However, the NRS was statistically significantly different, although not clinically significant, for patients undergoing major surgeries (mastectomies or tumorectomies with axillary clearance) (n = 29, 3.0 0.0-4.0 vs 4.0 2.0-5.0, P = 0.04). Morphine consumption during recovery did not differ (1.5 mg 0.0-6.0 mg vs 3.0 mg 0.0-6.0 mg, P = 0.20), except in the major surgery subgroup (1.5 mg 0.0-6.0 mg vs 6.0 mg 0.0-12.0 mg, P = 0.016). Intraoperative sufentanil and cumulative morphine consumption up to 24 hours did not differ between the 2 groups. Three patients experienced complications related to the Pecs I.
Pecs I is not better than a saline placebo in the presence of multimodal analgesia for breast cancer surgery. However, its role in extended (major) breast surgery may warrant further investigation.
This study was registered at ClinicalTrials.gov, identifier NCT01670448.
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