Growing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context.We investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients' outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh-Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline).Among the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients' biopsies. Shh was significantly (p < 0.05) enriched in youth (age < 68), male, nonsmokers, patients with a PS > 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response.These data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI.
Abstract Gastritis constitutes the initial step of the gastric carcinogenesis process. Gastritis diagnosis is based on histological examination of biopsies. Non-invasive real-time methods to detect mucosal inflammation are needed. Tissue optical properties modify reemitted light, i.e. the proportion of light that is emitted by a tissue after stimulation by a light flux. Analysis of light reemitted by gastric tissue could predict the inflammatory state. The aim of our study was to investigate a potential association between reemitted light and gastric tissue inflammation. We used two models and three multispectral analysis methods available on the marketplace. We used a mouse model of Helicobacter pylori infection and included patients undergoing gastric endoscopy. In mice, the reemitted light was measured using a spectrometer and a multispectral camera. We also exposed patient’s gastric mucosa to specific wavelengths and analyzed reemitted light. In both mouse model and humans, modifications of reemitted light were observed around 560 nm, 600 nm and 640 nm, associated with the presence of gastritis lesions. These results pave the way for the development of improved endoscopes in order to detect real-time gastritis without the need of biopsies. This would allow a better prevention of gastric cancer alongside with cost efficient endoscopies.
// Lei Wang 1, 2 , Coraline Dumenil 3 , Catherine Julié 4, 5 , Violaine Giraud 3 , Jennifer Dumoulin 3 , Sylvie Labrune 3 , Thierry Chinet 3, 5 , Jean-François Emile 4, 5 , Biao He 2 and Etienne Giroux Leprieur 3, 5 1 Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China 2 Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA 3 Department of Respiratory Diseases and Thoracic Oncology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France 4 Department of Pathology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France 5 EA 4340 "Biomarqueurs en Cancérologie et Onco-Hématologie" UVSQ, Paris-Saclay University, Boulogne-Billancourt, France Correspondence to: Etienne Giroux Leprieur, email: etienne.girouxleprieur@aphp.fr Keywords: lung cancer; circulating tumor cells; prognosis; predictive marker; molecular diagnosis Received: August 05, 2017 Accepted: September 20, 2017 Published: November 23, 2017 ABSTRACT Molecular characterization of tumor cells is a key step in the diagnosis and optimal treatment of lung cancer. However, analysis of tumor samples, often corresponding to small biopsies, can be difficult and does not accurately reflect tumor heterogeneity. Recent studies have shown that isolation of circulating tumor cells (CTCs) is feasible in non-small cell lung cancer patients, even at early disease stages. The amount of CTCs corresponds to the metastatic potential of the tumor and to patient prognosis. Moreover, molecular analyses, even at the single-cell level, can be performed on CTCs. This review describes the technologies currently available for detecting and capturing CTCs, the potential for downstream molecular diagnostics, and the clinical applications of CTCs isolated from lung cancer patients as screening, prognostic, and predictive tools. Main limitations of CTCs are also discussed.
(Fourme, Vieillard-Baron, Loubieres, Page) Intensive Care Unit.(Julie) Department of Pathology.(Jardin) Professor, Intensive Care Unit.Received from the Intensive Care Unit and the Department of Pathology, Hopital Ambroise Pare, Boulogne, France. Submitted for publication October 27, 1997. Accepted for publication May 6, 1998.Address reprint requests to Dr. Fourme: Intensive Care Unit, Ambroise Pare hospital, 9 Avenue Charles de Gaulle, 92700, Boulogne, France.Key words: Bronchoalveolar lavage; computed tomography of the chest; fat embolism syndrome; liposuction.FAT embolism syndrome (FES) is an uncommon and severe complication that occurs mainly in patients with long-bone fractures. This clinical syndrome includes acute respiratory failure, global neurologic dysfunction, and petechial rash following the precipitating event by 12 to 72 h. Nevertheless, one or more of these findings may be absent, making the diagnosis difficult to establish clinically, particularly after a surgical procedure such as liposuction. The authors report a case of isolated acute dyspnea early after liposuction.A 29-yr-old woman who was a healthy ballet-dancer without previous significant medical history underwent suction lipectomy of the abdomen, hips, and trocanteric area. The operation was uneventful, removing a total of only 600 ml of fatty tissue. Anesthesia (which lasted 2 h) consisted of fentanyl, midazolam, propofol (loading dose of 2 mg/kg and then 5 mg [middle dot] kg (-1) [middle dot] h-1infusion), and atracurium. There was no blood loss. Total volume of intravenous fluids intraoperatively and postoperatively were 1,500 ml, and urine output was 500 ml. Intraoperative oxygen saturations were 95-99%. One hour postoperatively, while breathing room air, the patient felt suddenly anxious and short of breath, oxygen saturation by pulse oximetry (SpO2) decreased from 93% to 82%, without hemodynamic change. A pulmonary embolism was eliminated immediately by pulmonary angiography. The patient was admitted to the intensive care unit for management and diagnosis. At examination, she was dyspneic, with a respiratory rate of 25 breaths/min, a blood pressure of 110/60 mmHg and a heart rate of 95 beats/min. Mental status was normal without focal neurologic signs. No petechiae was found. Lung auscultation revealed diffuse inspiratory rales. Temperature was 38.5 [degree sign]C. Arterial blood gas analysis while the patient was breathing 81 breaths/min of oxygen indicated that the pH was 7.44, arterial oxygen tension (PaO2) was 62 mmHg, arterial carbon dioxide tension (PaCO2) was 31 mmHg, and bicarbonate (HCO3-) was 24 mM. Chest roentgenography showed diffuse bilateral pulmonary alveolointerstitial infiltrates. Electrocardiography was normal, with sinus tachycardia (95 beats/min). Doppler echocardiography was normal without right ventricular enlargement. Left ventricular ejection fraction was normal, and systolic pulmonary artery pressure was 27 mmHg. Computed tomography of the chest (Figure 1) revealed patchy bilateral ground glass densities, macronodular opacities, and alveolar consolidation without pleural effusion.Bronchoalveolar lavage, performed 15 h after (Figure 2), was hemorrhagic with 520 103/ml(59% macrophages, 27% neutrophils, 14% lymphocytes); 60% of the macrophages contained red fat droplets after staining with an Oil Red O stain. Protected minibronchoalveolar lavage samples were sterile on the culture.Serum total calcium and cholesterol concentrations were decreased to 2.02 mM and 3.5 mM, respectively. C reactive protein was increased to 30 mg/l (N < 10). Hemoglobin level was the same level before and after the procedure (11 g/dl) and there was no thrombocytopenia. Fundoscopic evaluation results were normal. No fat globules were found in the urine.The patient's symptoms improved rapidly with trivial fluid support and supplementary oxygen. Results of chest radiography and blood gas analysis returned to normal within 2 days and allowed early hospital discharge on day 3. Subsequent chest computed tomography was normal 10 days after the acute event.Fat embolism syndrome severity can vary from mild adult respiratory distress syndrome to profound refractory hypoxemia leading to coma and death. Rupture of vessels and damage to adipocytes allow microthombi of lipids to enter the venous circulation. After being trapped in the pulmonary capillaries and hydrolyzed by a pulmonary lipase, free fatty acids cause direct toxic damage of the microvascular and alveolocapillary units and subsequently cause release of vasoactive amines and prostaglandins. The histopathology of FES is characterized by interstitial edema, transudate, and later exudate in the alveoli, the death of type II pneumocytes, and hyaline membrane formation. [1]Fat embolism syndrome is a well-known complication of traumatic injuries (1% to 35% after long-bone fractures [2,3]), cardiopulmonary resuscitation, or lipid infusion for parenteral feeding [4]but seems to be quite rare after liposuction, only five cases have been reported. [5,6,7,8,9]Of these five cases, four were suspected after evidence of adult respiratory distress syndrome with fever was seen, the fifth after transient, focal neurologic signs were noted after surgery. The latter was diagnosed during fundoscopic evaluation, others were diagnosed during autopsy, pulmonary arteriography, or chest radiography without further investigation. Four patients survived. This patient with FES underwent isolated liposuction without other combined procedures, as described in the other case reports. It does not agree with the assumption that FES after liposuction occurs only after time-consuming, multiple and combined procedures, such as mastopexie or abdominoplasty. [10]The five reports plus ours emphasized the difficulty of making the diagnosis of FES postoperatively. Many of the diagnostic criteria are insensitive and may reflect response to trauma rather than fat embolism per se. The classic clinical triad occurs within 48 h in only 85% of patients, after a free interval of 12 - 30 h after injury. [11]In our patient, acute respiratory failure was isolated and occurred immediately after the procedure with concomitant infiltrates seen on the chest X-ray. This finding indicates that the inflammatory process might begin earlier than previously reported. It is consistent with experimental data that show that oleic acid-induced pulmonary edema occurs less than 1 h after injection. [12]In patients with isolated respiratory symptoms, the presence of hypoxemia and pulmonary infiltrates are easily confused with other more commonly encountered problems, such as aspiration pneumonia, left ventricular overload with pulmonary edema, lung contusion, or massive transfusion. In the current case, normal echocardiography excluded heart failure, and sterile, protected minibronchoalveolar lavage eliminated sepsis. Moreover, the outcome was simple without specific therapy. To further establish the diagnosis of FES, bronchoalveolar lavage was performed, and contributed to the diagnosis.This case report emphasizes that microscopic evaluation of cells obtained by bronchoalveolar lavage allows rapid identification of patients with FES. According to Chastre et al., [13]a cut-off point of 5% of cells containing fat droplets was the diagnosis of FES. In our patient, the high percentage (60%) of cells containing fat droplets contrasted with the limited surgical procedure. Nevertheless, no data are available concerning normal bronchoalveolar lavage fat stain after uneventful liposuction. Although Vedrinne et al. [14]reported that bronchoalveolar lavage is not a reliable method for diagnosis of FES and that many conditions are associated with fat droplets in alveolar macrophages (multiple organ failure, sepsis, trauma, neoplasia, lipid infusion, or hypertriglyceridemia), historic background, clinical pattern, and chest imaging results are highly suggestive of this diagnosis. We considered the liposuction to have caused this FES rather than the propofol, which has been described to be an explanation for lipid deposition, but only during long-term infusion. [15]In conclusion, after liposuction, the incidence of FES might be underestimated because this diagnosis is not systematically considered and because the clinical pattern of FES often is not specific.
Abstract Background The identification of genomic signatures of colorectal cancer for risk stratification requires the study of large series of cancer patients with an extensive clinical follow-up. Multicentric clinical studies represent an ideal source of well documented archived material for this type of analyses. Methods To verify if this material is technically suitable to perform matrix-CGH, we performed a pilot study using macrodissected 29 formalin-fixed, paraffin-embedded tissue samples collected within the framework of the EORTC-GI/PETACC-2 trial for colorectal cancer. The scientific aim was to identify prognostic genomic signatures differentiating locally restricted (UICC stages II-III) from systemically advanced (UICC stage IV) colorectal tumours. Results The majority of archived tissue samples collected in the different centers was suitable to perform matrix-CGH. 5/7 advanced tumours displayed 13q-gain and 18q-loss. In locally restricted tumours, only 6/12 tumours showed a gain on 13q and 7/12 tumours showed a loss on 18q. Interphase-FISH and high-resolution array-mapping of the gain on 13q confirmed the validity of the array-data and narrowed the chromosomal interval containing potential oncogenes. Conclusion Archival, paraffin-embedded tissue samples collected in multicentric clinical trials are suitable for matrix-CGH analyses and allow the identification of prognostic signatures and aberrations harbouring potential new oncogenes.
This study was designed to evaluate prospectively magnetic resonance imaging for the prediction of the circumferential resection margin in rectal cancer to identify in which patient magnetic resonance imaging could accurately assess the circumferential resection margin before surgery and in which patients it could not.During a 17-month period, a preoperative magnetic resonance imaging for the assessment of circumferential resection margin was obtained prospectively in 38 patients with mid or low rectal cancer. The agreement of magnetic resonance imaging and pathologic examination for assessment of circumferential resection margin was analyzed.Overall, magnetic resonance imaging agreed with histologic examination of the circumferential resection margin assessment in 28 patients (73 percent; kappa = 0.47). In all cases of disagreement between magnetic resonance imaging and pathology, magnetic resonance imaging overestimated the circumferential resection margin involvement. For the 11 patients with mid rectal cancer, circumferential resection margin was well predicted by magnetic resonance imaging in all cases (kappa = 1). For 27 patients with low rectal tumor, overall agreement between magnetic resonance imaging and histologic assessment was 63 percent (kappa = 0.35). Agreement was 22 percent (kappa = 0.03) for the 9 patients with low anterior and 83 percent (kappa = 0.67) for the 18 patients with low posterior rectal tumor. Univariate analysis revealed that only low and anterior rectal tumor was risk factor of overestimation of the circumferential resection margin by magnetic resonance imaging.Although magnetic resonance imaging remains the best imaging tool for the preoperative assessment of the circumferential resection margin in patients with rectal cancer, it can overestimate the circumferential resection margin involvement in low and anterior tumor with the risk of overtreating the patients.
Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. It is often associated with a bad prognosis because of its asymptomatic phenotype until advanced stages, highlighting the need for its prevention and early detection. GC development is preceded by the emergence of gastric preneoplasia lesions (GPNLs), namely atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia (DYS). GC is currently diagnosed by endoscopy, which is invasive and costly and has limited effectiveness for the detection of GPNLs. Therefore, the discovery of non-invasive biomarkers in liquid biopsies, such as blood samples, in order to identify the presence of gastric preneoplasia and/or cancer lesions at asymptomatic stages is of paramount interest. This comprehensive review provides an overview of recently identified plasma/serum proteins and their diagnostic performance for the prediction of GPNLs and early cancer lesions. Autoantibodies appear to be promising biomarkers for AG, IM and early gastric cancer detection, along with inflammation and immunity-related proteins and antibodies against
