Distinguishing Benign from Malignant Pancreatic and Periampullary Lesions Using Combined Use of 1H-NMR Spectroscopy and Gas Chromatography–Mass Spectrometry

Previous work demonstrated that serum metabolomics can distinguish pancreatic cancer from benign disease. However, in the clinic, non-pancreatic periampullary cancers are difficult to distinguish from pancreatic cancer. Therefore, to test the clinical utility of this technology, we determined whether any pancreatic and periampullary adenocarcinoma could be distinguished from benign masses and biliary strictures. Sera from 157 patients with malignant and benign pancreatic and periampullary lesions were analyzed using proton nuclear magnetic resonance (1H-NMR) spectroscopy and gas chromatography–mass spectrometry (GC-MS). Multivariate projection modeling using SIMCA-P+ software in training datasets (n = 80) was used to generate the best models to differentiate disease states. Models were validated in test datasets (n = 77). The final 1H-NMR spectroscopy and GC-MS metabolomic profiles consisted of 14 and 18 compounds, with AUROC values of 0.74 (SE 0.06) and 0.62 (SE 0.08), respectively. The combination of 1H-NMR spectroscopy and GC-MS metabolites did not substantially improve this performance (AUROC 0.66, SE 0.08). In patients with adenocarcinoma, glutamate levels were consistently higher, while glutamine and alanine levels were consistently lower. Pancreatic and periampullary adenocarcinomas can be distinguished from benign lesions. To further enhance the discriminatory power of metabolomics in this setting, it will be important to identify the metabolomic changes that characterize each of the subclasses of this heterogeneous group of cancers

Personalized Oncogenomics: Clinical Experience with Malignant Peritoneal Mesothelioma Using Whole Genome Sequencing

<div><p>Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma-related genes <i>NF2</i>, <i>CDKN2A</i>, <i>LATS2</i>, amongst others, were identified. Activation of <i>MET</i>-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease.</p></div

Patient 2 pertinent radiology and pathology.

<p>(A)Vaginal mass biopsy showing malignant mesothelial cells with sarcomatoid features (H&E 20X). (B) CT/PET scan showing uptake in vaginal mass. (C) CT/PET showing additional uptake in the cecum. (D) Surgical specimen from the cecum showing epithelioid mesothelial proliferation with heavy lymphoplasmacytic infiltrate (H&E 20X). (E) Post-treatment CT/PET showing resolution of the vaginal mass (as compared to B). (F) Post-treatment CT/PET showing persistence of the cecal mass (compared with C). Imaging of associated inguinal lymphadenopathy not shown.</p

Patient 1 and 2 large-scale genomic alterations.

<p>Circos Plots for patients 1 (A) and 2 (B). Copy number gains shown in red, copy number losses shown in green (height of bars is proportional to the number of copies gained or lost). Purple lines indicate interchromosomal translocations. Orange lines indicate intrachromosomal translocation.</p

Select SNVs from patients 1 and 2.

<p><i>NF2</i> loss-of-function mutations were common to both patients, as well as mutations in <i>CNTNAP3B</i> (shown in bold). For a complete list of SNVs see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119689#pone.0119689.s003" target="_blank">S1 File</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119689#pone.0119689.s004" target="_blank">S2 File</a>.</p><p>Select SNVs from patients 1 and 2.</p

Patient 1 pertinent radiology and pathology.

<p>(A)Axial CT scan showing peritoneal-based pelvic mass. (B) Abdominal fluid aspiration biopsy showing papillary mesothelial proliferation (H&E stain on cell block preparation, 40X magnification). (C) Omental disease sampled at cytoreductive surgery showing malignant mesothelial cells forming gland-like structures, papillae, with spindle cell formation and sarcomatoid features. No treatment effect is appreciable (H&E 40X).</p