The unfolded protein response-glutathione metabolism axis: A novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms.

Platinum-based drugs remain the reference treatment for gastric cancer (GC). However, the frequency of resistance, due to mutations in TP53 or alterations in the energy and redox metabolisms, impairs the efficacy of current treatments, highlighting the need for alternative therapeutic options. Here, we show that a cycloruthenated compound targeting the redox metabolism, RDC11, induces higher cytotoxicity than oxaliplatin in GC cells and is more potent in reducing tumor growth in vivo. Detailed investigations into the mode of action of RDC11 indicated that it targets the glutathione (GSH) metabolism, which is an important drug resistance mechanism. We demonstrate that cycloruthenated complexes regulate the expression of enzymes of the transsulfuration pathway via the Unfolded Protein Response (UPR) and its effector ATF4. Furthermore, RDC11 induces the expression of SLC7A11 encoding for the cystine/glutamate antiporter xCT. These effects lead to a lower cellular GSH content and elevated oxygen reactive species production, causing the activation of a caspase-independent apoptosis. Altogether, this study provides the first evidence that cycloruthenated complexes target the GSH metabolism, neutralizing thereby a major resistance mechanism towards platinum-based chemotherapies and anticancer immune response.

Left-sided portal hypertension: Update and proposition of management algorithm.

Left-sided or segmental portal hypertension (SPHT) is a rare entity, most often associated with pancreatic disease or antecedent pancreatic surgery. The starting point is splenic vein obstruction secondary to local inflammation or, less often, extrinsic compression. SPHT leads to splenomegaly and development of collateral porto-systemic venous circulation. SPHT should be suspected in patients with pancreatic history who present with episodic upper gastrointestinal bleeding and splenomegaly with normal liver function tests. The most common clinical presentation is major upper gastrointestinal bleeding secondary to rupture of esophageal and/or gastric varices. At the present time, there are no management recommendations for SPHT, particularly when the patient is asymptomatic. In patients with upper gastro-intestinal bleeding, hemostasis can be obtained either by medical or interventional means according to patient status and available resources. For symptomatic patients, splenectomy is the reference treatment. Recently, less invasive, radiologic procedures, such as splenic artery embolization, have been developed as an alternative to surgery. Additionally, sonography-guided endoscopic hemostasis can also be envisioned, leading to the diagnosis and treatment of the lesion by elastic band ligation or by glue injection into the varices during the same procedure. The goal of this article is to describe the pathophysiological mechanisms behind SPHT and its clinical manifestations and treatment, based on a review of the literature. Because of the absence of recommendations for the management of SPHT, we propose a decisional algorithm for the management of SPHT based on the literature.

Sarcopenia remaining after intensive nutritional feeding support could be a criterion for the selection of patients for surgery for oesogastric junction adenocarcinoma.

BACKGROUND: Sarcopenia is recognized as a negative prognostic factor in several cancers. The aim of this study was to investigate the impact of nutritional support with feeding jejunostomy (FJ) on the occurrence of sarcopenia and how it may affect postoperative short-term outcomes and long-term survival outcomes in patients undergoing esophagectomy for oesogastric junction adenocarcinoma (OJA). METHODS: Patients with OJA were included. The presence of sarcopenia was determined using cutoff values of the total cross-sectional muscle tissue measured on CT scan. We analyzed risk factors for sarcopenia occurrence and the impact of preoperative sarcopenia on postoperative results, overall survival and disease-free survival. RESULTS: A total of 124 patients were eligible for analysis. Ninety-one patients underwent surgery after chemotherapy, and 72 of them received preoperative FJ. Among the 91 patients, 21 patients (23.0%) were sarcopenic after preoperative chemotherapy. Multivariate analysis showed that FJ is a protective factor against sarcopenia occurrence. Overall survival was significantly different between sarcopenic and nonsarcopenic patients (median survival = 33.7 vs. 58.6 months, respectively, p = 0.04), and sarcopenia occurrence was an independent risk factor for overall survival in patients who underwent surgery (HR = 3.02; CI 95% 1.55-5.9; p < 0.005). Subgroup analyses showed no differences in overall survival between patients who presented sarcopenia despite nutritional prehabilitation with a FJ and patients excluded from surgery in palliative situations (median survival = 21.9 vs. 17.2 months, respectively, p = 0.46). CONCLUSION: The persistence of sarcopenia after preoperative chemotherapy despite renutrition with FJ could be a selection factor to propose curative surgery for OJA.

Diffusion-weighted and gadolinium-enhanced dynamic MRI in parotid gland tumors.

PURPOSE: To evaluate the value of diffusion-weighted imaging and dynamic contrast-enhanced MRI for the diagnosis of parotid gland tumors. METHODS: Retrospective review of patients with surgically treated parotid tumors between January 2009 and June 2020, who underwent a preoperative parotid gland MRI including standard morphological sequences, diffusion-weighted echoplanar imaging with apparent diffusion coefficient measurement and T1-weighted gadolinium-enhanced dynamic MRI sequences with Fat Saturation. The lesion was classified between malignant vs benign and precisions regarding its histological type were given when possible. Imaging findings were compared with pathology results. RESULTS: Inclusion of 133 patients (mean age: 53 years). Multiparametric MRI had a sensitivity of 90.3%, a specificity of 77.5%, an overall accuracy of 80.5%, a positive predictive value of 54.9% and a negative predictive value of 96.3% to differentiate benign parotid tumor from malignant ones. Specificity (85.5%) and positive predictive value (67.6%) were improved for cases, where anatomical and functional MRI characteristics were conclusive and consistent with clinical findings. CONCLUSIONS: Combining diffusion-weighted and gadolinium-enhanced dynamic sequences, in addition to morphological ones enables high (> 90%) sensitivity to detect malignant parotid gland tumors. It also gives the possibility to characterize pleomorphic adenomas and Warthin tumors and to avoid fine-needle aspiration in cases of typical imaging presentation and reassuring clinical findings.

Robotically assisted augmented reality system for identification of targeted lymph nodes in laparoscopic gynecological surgery: a first step toward the identification of sentinel node : Augmented reality in gynecological surgery.

BACKGROUND: To prove feasibility of multimodal and temporal fusion of laparoscopic images with preoperative computed tomography scans for a real-time in vivo-targeted lymph node (TLN) detection during minimally invasive pelvic lymphadenectomy and to validate and enable such guidance for safe and accurate sentinel lymph node dissection, including anatomical landmarks in an experimental model. METHODS: A measurement campaign determined the most accurate tracking system (UR5-Cobot versus NDI Polaris). The subsequent interventions on two pigs consisted of an identification of artificial TLN and anatomical landmarks without and with augmented reality (AR) assistance. The AR overlay on target structures was quantitatively evaluated. The clinical relevance of our system was assessed via a questionnaire completed by experienced and trainee surgeons. RESULTS: An AR-based robotic assistance system that performed real-time multimodal and temporal fusion of laparoscopic images with preoperative medical images was developed and tested. It enabled the detection of TLN and their surrounding anatomical structures during pelvic lymphadenectomy. Accuracy of the CT overlay was > 90%, with overflow rates < 6%. When comparing AR to direct vision, we found that scores were significatively higher in AR for all target structures. AR aided both experienced surgeons and trainees, whether it was for TLN, ureter, or vessel identification. CONCLUSION: This computer-assisted system was reliable, safe, and accurate, and the present achievements represent a first step toward a clinical study.

Complete Laparoscopic Interval Debulking Surgery for Advanced Ovarian Cancer Achieves Similar Survival Outcomes to Open Approach: A Propensity-Matched Study.

To assess the laparoscopic interval debulking surgery (IDS) outcomes compared to laparotomy, by analyzing the overall survival (OS) and the progression free survival (PFS), as well as the intra- and post-operative morbidity.In this retrospective propensity-score-matched cohort study, all patients with stage III or IV FIGO (International Federation of Gynecology and Obstetrics) serous ovarian cancer, undergoing complete IDS after neoadjuvant chemotherapy, from January 1st of 2009 to June 1st 2019, were included.Thirty-seven patients were included in the laparoscopy group and 40 in the laparotomy group. There was no significant difference in terms of median OS between laparoscopy and laparotomy (23.1 months [95% CI 15.7-29.7] versus 26.3 months [95% CI 21.7-31.7], respectively, p = 0.17) and median PFS (14.8 months [95% CI 10.6-21.5] versus 12 months [95% CI 11-15.1], p = 0.057). After applying the propensity score, 25 patients were included in each group. Laparoscopy was associated with significantly less early postoperative complications (6 versus 17, p = 0.01) and shorter hospital stay (7.6 days versus 12.1, p < 0.001) and a significantly better OS (HR 0.45 [95% CI 0.19-0.95], p = 0.04), but with no significant difference in terms of PFS (HR 0.71 [95% CI 0.27-1.88], p = 0.49).In carefully-selected patients with advanced ovarian cancer, complete laparoscopic interval debulking surgery achieves similar survival outcomes to open laparotomy. Therefore, laparoscopy appears as a safe alternative to laparotomy for IDS after NACT in selected patients with advanced ovarian cancer and a low burden of disease.

Conventional and artificial intelligence-based imaging for biomarker discovery in chronic liver disease.

Chronic liver diseases, resulting from chronic injuries of various causes, lead to cirrhosis with life-threatening complications including liver failure, portal hypertension, hepatocellular carcinoma. A key unmet medical need is robust non-invasive biomarkers to predict patient outcome, stratify patients for risk of disease progression and monitor response to emerging therapies. Quantitative imaging biomarkers have already been developed, for instance, liver elastography for staging fibrosis or proton density fat fraction on magnetic resonance imaging for liver steatosis. Yet, major improvements, in the field of image acquisition and analysis, are still required to be able to accurately characterize the liver parenchyma, monitor its changes and predict any pejorative evolution across disease progression. Artificial intelligence has the potential to augment the exploitation of massive multi-parametric data to extract valuable information and achieve precision medicine. Machine learning algorithms have been developed to assess non-invasively certain histological characteristics of chronic liver diseases, including fibrosis and steatosis. Although still at an early stage of development, artificial intelligence-based imaging biomarkers provide novel opportunities to predict the risk of progression from early-stage chronic liver diseases toward cirrhosis-related complications, with the ultimate perspective of precision medicine. This review provides an overview of emerging quantitative imaging techniques and the application of artificial intelligence for biomarker discovery in chronic liver disease.

Current Clinical and Pre-Clinical Imaging Approaches to Study the Cancer-Associated Immune System.

In the light of the success and the expected growth of its arsenal, immuno-therapy may become the standard neoadjuvant procedure for many cancers in the near future. However, aspects such as the identity, organization and the activation status of the peri- and intra-tumoral immune cells would represent important elements to weigh in the decision for the appropriate treatment. While important progress in non-invasive imaging of immune cells has been made over the last decades, it falls yet short of entering the clinics, let alone becoming a standard procedure. Here, we provide an overview of the different intra-vital imaging approaches in the clinics and in pre-clinical settings and discuss their benefits and drawbacks for assessing the activity of the immune system, globally and on a cellular level. Stimulated by further research, the future is likely to see many technological advances both on signal detection and emission as well as image specificity and resolution to tackle current hurdles. We anticipate that the ability to precisely determine an immune stage of cancer will capture the attention of the oncologist and will create a change in paradigm for cancer therapy.

Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer.

The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was to gain information on the impact of cisplatin and the pan-HDACi SAHA (suberanilohydroxamic acid) on the tumor substructure and microenvironment of GC, by establishing patient-derived xenografts of GC and a combination of ultrasound, immunohistochemistry, and transcriptomics to analyze. The tumors responded partially to SAHA and cisplatin. An ultrasound gave more accurate tumor measures than a caliper. Importantly, an ultrasound allowed a noninvasive real-time access to the tumor substructure, showing differences between cisplatin and SAHA. These differences were confirmed by immunohistochemistry and transcriptomic analyses of the tumor microenvironment, identifying specific cell type signatures and transcription factor activation. For instance, cisplatin induced an "epithelial cell like" signature while SAHA favored a "mesenchymal cell like" one. Altogether, an ultrasound allowed a precise follow-up of the tumor progression while enabling a noninvasive real-time access to the tumor substructure. Combined with transcriptomics, our results underline the different intra-tumoral structural changes caused by both drugs that impact differently on the tumor microenvironment.

Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer.

Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960's. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene TP53 to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes-as well complexes with other metals (osmium, iron, platinum)-can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the ER after entering the cell using passive and active mechanisms. These particular physico-chemical properties of the organometallic complexes designed by Dr. Pfeffer contribute to their ability to reduce tumor growth and angiogenesis. Taken together, the pioneering work of Dr. Michel Pfeffer over his career provides us with a legacy that we have yet to fully embrace.

Present and future of the labyrinth imaging: Focus on the use of T2-weighted and contrast-enhanced delayed FLAIR (1 h) sequences.

OBJECTIVE: Part of the recent progress in the labyrinth imaging has been made possible by the rise of contrast-free T2-weighted and delayed (1h) FLAIR sequences. The aim of this article is to review evidence for the use of these two sequences to image the inner ear, especially the posterior membranous labyrinth. MATERIAL AND METHODS: We analyzed MRI-based papers (2007-2020)using high-resolution T2-weighted or contrast-enhanced FLAIR (1h) sequences to image the inner ear. RESULTS: T2-weighted sequences (3T MRI)enabled the visualization of the posterior membranous labyrinth with good correlation when compared to corresponding histological slices.Significant progress has been made, especially in terms of scanning time, aiming at reducing it, in order to decrease motions artifacts. The saccule is visible on a 3T MRI without significant motion artifacts. Its shape is ovoid, with a maximum height and width of 1.6 and 1.4 mm, respectively. An enlarged saccule was observed in 84%of patients with unilateral Meniere's disease, in 28%of patients with vestibular schwannomas (VS) and 47%of patients with intralabyrinthine schwannomas. VS obstructing the internal auditory canal caused a decrease of the perilymphatic signal (more moderate decrease in meningiomas) on T2 gradient-echo images. Contrast-enhanced FLAIR sequences are useful to image vestibular/facial neuritis and inflammatory inner ear diseases. CONCLUSION: Precise analysis of the posterior membranous labyrinth, in terms of size, shape and signal intensity, is possible on a 3T MRI using high-resolution gradient-echo T2-weighted sequences. Such sequences are an interesting add-on to delayed (4h30) FLAIR-based protocols for labyrinth imaging.

An image-guided (CT) assessment of a new asymmetric balloon for the treatment of epistaxis.

PURPOSE: The main objective was to perform an image-guided (CT) assessment of the efficacy of the CAVI-T™ balloon to compress the sphenopalatine artery (SPA) on cadaver heads, for the management of epistaxis. The secondary objectives were to analyse the deployment and stability of this balloon according to the volume injected into the nasal cavity, to optimise its use. METHODS: A descriptive anatomical study was performed. The catheterization of the SPA was performed on four fresh-frozen heads with a SPA approach through the maxillary sinus, leaving the nasal cavity unscathed. Computed Tomography images were acquired without and with the balloon, inflated by injections of progressive volumes of diluted iodine, for optimal contrast with the surrounding tissues. We evaluated the positioning of the balloon according to two predetermined markers on the device. RESULTS: Out of 68 image-guided acquisitions, the CAVI-T™ balloon compressed the SPA in 88% of cases. The other nasal cavity structures were compressed in 86% to 100% of the cases, depending on the positioning of the CAVI-T™ balloon, therefore allowing a complete obstruction of the nasal cavity. The device remained stable upon inflation and did not obstruct the nasopharynx. CONCLUSION: The CAVI-T™ balloon provided effective compression of the SPA and the different structures of the nasal cavity.

New Compartmental Reading Method for MRI Enables Accurate Localization of Cholesteatomas With High Sensitivity and Specificity.

OBJECTIVES: Cholesteatoma is an inflammatory disease, frequently observed in childrens and young adults, with a risk of relapse or recurrence. The few studies which analyzed cholesteatoma localization on magnetic resonance imaging (MRI) usually merged CT-MR images or relied on their authors' anatomical knowledge. We propose a compartmental reading method of the compartments of the middle ear cavity for an accurate localization of cholesteatomas on MR images alone. MATERIAL AND METHODS: Our method uses easily recognizable anatomical landmarks, seen on both computed tomography (CT) and MRI, to delimit the middle ear compartments (epitympanum, mesotympanum, hypotympanum, retrotympanum, protympanum, antrum-mastoid cavity). We first tested it on 50 patients on non-enhanced temporal bone CT. Then, we evaluated its performances for the localization of cholesteatomas on MRI, compared with surgery on 31 patients (validation cohort). RESULTS: The selected anatomical landmarks that delimited the middle ear compartments were applicable in 98 to 100% of the cases. In the validation cohort, we were able to accurately localize the cholesteatoma on MRI in 83% of the cases (n = 26) with high sensitivity (95.7%) and specificity (98.6%). CONCLUSION: With our compartmental reading method, based on the recognition of well-known anatomical landmarks to differentiate the compartments of the middle ear cavity on MRI, we were able to accurately localize the cholesteatoma with high (>90%) sensitivity and specificity. Such landmarks are widely applicable and only require limited learning time based on key images. Accurate localization of the cholesteatoma is useful for the choice of surgical approach.

The dynamics of endolymphatic hydrops and vestibular disorders.

Endolymphatic hydrops is defined as an accumulation of endolymph in the inner ear leading to a buildup of pressure and distortion of intralabyrinthine structures. The pressure variation is neither obvious nor easy to measure and remains not clearly confirmed. The distortion of endolymphatic structures has been the main described phenomenon since Hallpike, Cairns and Yamakawa in 1938. However, some clinical symptoms associated with endolymphatic hydrops are in addition to the typical triad of symptoms of Meniere's disease. This introduction to the state of the art is an analysis of the relationship between hydrops and clinical vestibular disorders, with a focus on the dynamics of endolymphatic hydrops. The distortion of endolabyrinthine structures can be considered as a dynamic process modeled with mechanical elastic behavior.

Vestibular schwannomas with spontaneous shrinkage: about 35 cases.

PURPOSES: The first aim is to describe the epidemiological, clinical, and radiological characteristics of regressive vestibular schwannomas (VS), based on volumetric measurements on MRI to define which regressions are significant. The secondary aim is to look for a correlation between a shrinkage of the tumor and the medical history, and the presence of clinical symptoms. METHODS: We first selected all patients presenting with a VS who underwent two or more MRI of the internal auditory canal on the same 3 T MRI machine retrospectively between January 2013 and June 2018. All MRI images were evaluated independently by two radiologists. The volumetric analysis was performed contrast-enhanced 2D spin-echo T1-weighted sequence and expressed in cubic centimeters. RESULTS: Thirty-five patients presented with a regressive VS on MRI (14%). The annual mean shrinkage rate was 0.08 cm3/year. Eighty percent of the patients present both a shrinkage by more than 0.01 cm3/year and a decrease of the initial tumor volume by more than 20%. The majority of patients are asymptomatic or presented moderate balance disorders, which remained stable or improved over time. Tinnitus was observed in 47% and was stable or improved in the majority of cases and the mean annual mean hearing loss was by < or = 4 dB/year. CONCLUSION: Out of 247 VS, 14% decreased using follow-up (by > or = 2 MRI), and a spontaneous shrinkage greater than 0.01 cm3/year and greater than 20% could be considered significant.