Gene expression profiling of patient‐derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts

Abstract c‐MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient‐derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC‐high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC‐low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC‐high group and six transcripts increased in the MYC‐low group. We validated the ability of these markers panel to identify MYC‐high patient‐derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC‐high patients are more sensitive to JQ1 treatment compared to MYC‐low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics

Transplanted lungs and the ``white plague'' A case-report and review of the literature

International audienceRationale: Solid organ transplant recipients, especially after lung transplantation, are at increased risk for Mycobacterium tuberculosis pulmonary tuberculosis due to lifelong immunosuppression.Patient concerns: A 41-year-old woman underwent a second bilateral lung transplantation that was complicated by fatal pulmonary tuberculosis.Diagnoses: Histological examination of a lung biopsy performed 6 weeks after retransplantation revealed a caseating granuloma and necrosis. Acid-fast bacilli were identified as rifampicin-susceptible M. tuberculosis by real-time polymerase chain reaction (PCR), confirmed by culture 2 weeks later.Interventions: Our investigation led us to highly suspect that the transplanted lungs were the source of M. tuberculosis transmission.Lessons: In order to optimize diagnosis and treatment for lung recipients with latent or active tuberculosis, regular assessment of lower respiratory samples for M. tuberculosis, particularly during the 12-month period posttransplant should be implemented. Regarding donor-derived transmission, screening donor grafts with latent tuberculosis by M. tuberculosis real-time PCR in lymphoid and adipose tissues is an option that should be considered

Pathological effects of lung radiofrequency ablation that contribute to pneumothorax, using a porcine model

International audienceObjectives: The incidence of pneumothorax is 7 times higher after lung radiofrequency ablation (RFA) than after lung biopsy. The reasons for such a difference have never been objectified. The histopathologic changes in lung tissue are well-studied and established for RF in the ablation zone. However, it has not been previously described what the nature of thermal injury might be along the shaft of the RF electrode as it traverses through normal lung tissue to reach the ablation zone. The purpose of this study was to determine the changes occurring around the RF needle along the pathway between the ablated zone and the pleura.Material and methods: In 3 anaesthetised and ventilated swine, 6 RFA procedures (right and left lungs) were performed using a 14-gauge unipolar multi-tined retractable 3 cm radiofrequency LeVeen probe with a coaxial introducer positioned under CT fluoroscopic guidance. In compliance with literature guidelines, we implemented a gradually increasing thermo-ablation protocol using a RF generator. Helical CT images were acquired pre- and post-RFA procedure to detect and evaluate pneumothorax. Four percutaneous 19-gauge lung biopsies were also performed on the fourth swine under CT guidance. Swine were sacrificed for lung ex vivo examinations, scanning electron microscopy (SEM) and pathological analysis.Results: Three severe (over 50 ml) pneumothorax were detected after RFA. In each one of them, pathological examination revealed a fistulous tract between ablation zone and pleura. No fistulous tract was observed after biopsies. In the 3 cases of severe pneumothorax, the tract was wide open and clearly visible on post procedure CT images and SEM examinations. The RFA tract differed from the needle biopsy tract. The histological changes that are usually found in the ablated zone were observed in the RFA tract’s wall and were related to thermal lesions. These modifications caused the creation of a coagulated pulmonary parenchyma rim between the thermo-ablation zone and the pleural space. The structural properties of the damage can explain why the RFA tract is remains patent after needle withdrawal.Conclusion: Our study demonstrates for the first time that the changes around the RF needle are the same as in the ablated zone. The damage could create fistulous tracts along the needle path between thermo-ablation zone and pleural space. These fistulas could certainly be responsible for severe pneumothorax that occurs in many patients treated with lung RFA

Rapid Diagnosis of Lung Tumors, a Feasability Study Using Maldi-Tof Mass Spectrometry

International audienceObjective Despite recent advances in imaging and core or endoscopic biopsies, a percentage of patients have a major lung resection without diagnosis. We aimed to assess the feasibility of a rapid tissue preparation/analysis to discriminate cancerous from non-cancerous lung tissue. Methods Fresh sample preparations were analyzed with the Microflex LTTM MALDI-TOF analyzer. Each main reference spectra (MSP) was consecutively included in a database. After definitive pathological diagnosis, each MSP was labeled as either cancerous or non-cancerous (normal, inflammatory, infectious nodules). A strategy was constructed based on the number of concordant responses of a mass spectrometry scoring algorithm. A 3-step evaluation included an internal and blind validation of a preliminary database (n = 182 reference spectra from the 100 first patients), followed by validation on a whole cohort database (n = 300 reference spectra from 159 patients). Diagnostic performance indicators were calculated. Results 127 cancerous and 173 non-cancerous samples (144 peripheral biopsies and 29 inflammatory or infectious lesions) were processed within 30 minutes after biopsy sampling. At the most discriminatory level, the samples were correctly classified with a sensitivity, specificity and global accuracy of 92.1%, 97.1% and 95%, respectively. Conclusions The feasibility of rapid MALDI-TOF analysis, coupled with a very simple lung preparation procedure, appears promising and should be tested in several surgical settings where rapid on-site evaluation of abnormal tissue is required. In the operating room, it appears promising in case of tumors with an uncertain preoperative diagnosis and should be tested as a complementary approach to frozen-biopsy analysis

Detection of EGFR, KRAS and BRAF mutations in metastatic cells from cerebrospinal fluid

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Severe Pulmonary Fibrosis as the First Manifestation of Interferonopathy (TMEM173 Mutation)

International audienceWe report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after. Recognized causes of familial interstitial lung disease were all excluded. All three subjects had a mutation in the previously described autoinflammatory disease called SAVI (stimulator of interferon genes [STING]-associated vasculopathy with onset in infancy). These cases emphasize the need to consider this possibility in children and young adults with lung fibrosis after common causes have been ruled out

LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker

International audiencePancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell–promoting factor LIF supports PDAC-associated neural remodeling (PANR). LIF was overex-pressed in tumor tissue compared with healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral nerves. Cancer cells and stromal cells in PDAC tissues both expressed LIF, but only stromal cells could secrete it. Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area. Notably, injection of LIF-blocking antibody into PDAC-bearing mice reduced intratumoral nerve density, supporting a critical role for LIF function in PANR. In serum from human PDAC patients and mouse models of PDAC, we found that LIF titers positively correlated with intratumoral nerve density. Taken together, our findings suggest LIF as a candidate serum biomarker and diagnostic tool and a possible therapeutic target for limiting the impact of PANR in PDAC pathophysiology and metastatic progression. Significance: This study suggests a target to limit neural remodeling in pancreatic cancer, which contributes to poorer quality of life and heightened metastatic progression in patients

Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions

International audienceTissue architecture contributes to pancreatic ductal adenocarcinoma (PDAC) phenotypes. Cancer cells within PDAC form gland-like structures embedded in a collagen-rich meshwork where nutrients and oxygen are scarce. Altered metabolism is needed for tumour cells to survive in this environment, but the metabolic modifications that allow PDAC cells to endure these conditions are incompletely understood. Here we demonstrate that collagen serves as a proline reservoir for PDAC cells to use as a nutrient source when other fuels are limited. We show PDAC cells are able to take up collagen fragments, which can promote PDAC cell survival under nutrient limited conditions, and that collagen-derived proline contributes to PDAC cell metabolism. Finally, we show that proline oxidase (PRODH1) is required for PDAC cell proliferation in vitro and in vivo. Collectively, our results indicate that PDAC extracellular matrix represents a nutrient reservoir for tumour cells highlighting the metabolic flexibility of this cancer

Shape of Fluorescent signals in the perilesional lung and the associated targeted lesions.

<p>^a. Comparison of the percentage of each shape between perilesional lung parenchyma and targeted lesions. Statistical analysis using the Pearson χ². statistical significance defined as * p<0,01, ** p<0,001, ***p<0,0001.</p><p>^b. Comparison of the percentage of each shape between NSLC and non-tumoral lesions and lung metastases. Statistical analysis using the Pearson χ². Statistical significance defined as ^§p = 0,02, ^§§p<0,01, ^§§§p<0,001.</p><p>NSCLC: Non Small Cell Lung Cancer. PB: Photobleaching.</p