The treatment of achalasia patients with esophageal varices: an international study

Background: Treatment options for achalasia include endoscopic and surgical techniques that carry the risk of esophageal bleeding and perforation. The rare coexistence of esophageal varices has only been anecdotally described and treatment is presumed to carry additional risk. Methods: Experience from physicians/surgeons treating this rare combination of disorders was sought through the International Manometry Working Group. Results: Fourteen patients with achalasia and varices from seven international centers were collected (mean age 61 9 years). Five patients were treated with botulinum toxin injections (BTI), four had dilation, three received peroral endoscopic myotomy (POEM), one had POEM then dilation, and one patient underwent BTI followed by Heller’s myotomy. Variceal eradication preceded achalasia treatment in three patients. All patients experienced a significant symptomatic improvement (median Eckardt score 7 vs 1; p < 0.0001) at 6 months follow-up, with treatment outcomes resembling those of 20 non- cirrhotic achalasia patients who underwent similar therapy. No patients had recorded complications of bleeding or perforation. Conclusion: This study shows an excellent short-term symptomatic response in patients with esophageal achalasia and varices and demonstrates that the therapeutic outcomes and complications, other than transient encephalopathy in both patients who had a portosystemic shunt, did not differ to disease-matched patients without varices

Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral Latent Membrane Protein 1 and the immunomodulatory protein galectin 9

BACKGROUND: Nasopharyngeal carcinomas (NPC) are consistently associated with the Epstein-Barr virus (EBV). Their malignant epithelial cells contain the viral genome and express several antigenic viral proteins. However, the mechanisms of immune escape in NPCs are still poorly understood. EBV-transformed B-cells have been reported to release exosomes carrying the EBV-encoded latent membrane protein 1 (LMP1) which has T-cell inhibitory activity. Although this report suggested that NPC cells could also produce exosomes carrying immunosuppressive proteins, this hypothesis has remained so far untested. METHODS: Malignant epithelial cells derived from NPC xenografts – LMP1-positive (C15) or negative (C17) – were used to prepare conditioned culture medium. Various microparticles and vesicles released in the culture medium were collected and fractionated by differential centrifugation. Exosomes collected in the last centrifugation step were further purified by immunomagnetic capture on beads carrying antibody directed to HLA class II molecules. Purified exosomes were visualized by electron microscopy and analysed by western blotting. The T-cell inhibitory activities of recombinant LMP1 and galectin 9 were assessed on peripheral blood mononuclear cells activated by CD3/CD28 cross-linking. RESULTS: HLA-class II-positive exosomes purified from C15 and C17 cell supernatants were containing either LMP1 and galectin 9 (C15) or galectin 9 only (C17). Recombinant LMP1 induced a strong inhibition of T-cell proliferation (IC50 = 0.17 nM). In contrast recombinant galectin 9 had a weaker inhibitory effect (IC50 = 46 nM) with no synergy with LMP1. CONCLUSION: This study provides the proof of concept that NPC cells can release HLA class-II positive exosomes containing galectin 9 and/or LMP1. It confirms that the LMP1 molecule has intrinsic T-cell inhibitory activity. These findings will encourage investigations of tumor exosomes in the blood of NPC patients and assessment of their effects on various types of target cells

Long-term follow-up after endoscopic resection for superficial esophageal squamous cell carcinoma: a multicenter Western studyAbstract

Background Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are the first-line treatments for superficial esophageal squamous cell carcinoma (SCC). This study aimed to compare long-term clinical outcome and oncological clearance between EMR and ESD for the treatment of superficial esophageal SCC. Methods We conducted a retrospective multicenter study in five French tertiary care hospitals. Patients treated by EMR or ESD for histologically proven superficial esophageal SCC were included consecutively. Results Resection was performed for 148 tumors (80 EMR, 68 ESD) in 132 patients. The curative resection rate was 21.3 % in the EMR group and 73.5 % in the ESD group (P &lt; 0.001). The recurrence rate was 23.7 % in the EMR group and 2.9 % in the ESD group (P = 0.002). The 5-year recurrence-free survival rate was 73.4 % in the EMR group and 95.2 % in the ESD group (P = 0.002). Independent factors for cancer recurrence were resection by EMR (hazard ratio [HR] 16.89, P = 0.01), tumor infiltration depth ≥ m3 (HR 3.28, P = 0.02), no complementary treatment by chemoradiotherapy (HR 7.04, P = 0.04), and no curative resection (HR 11.75, P = 0.01). Risk of metastasis strongly increased in patients with tumor infiltration depth ≥ m3, and without complementary chemoradiotherapy (P = 0.02). Conclusion Endoscopic resection of superficial esophageal SCC was safe and efficient. Because it was associated with an increased recurrence-free survival rate, ESD should be preferred over EMR. For tumors with infiltration depths ≥ m3, chemoradiotherapy reduced the risk of nodal or distal metastasis

Imaging alternatives to colonoscopy: CT colonography and colon capsule. European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Guideline – Update 2020

1. ESGE/ESGAR recommend computed tomographic colonography (CTC) as the radiological examination of choice for the diagnosis of colorectal neoplasia. Strong recommendation, high quality evidence. ESGE/ESGAR do not recommend barium enema in this setting. Strong recommendation, high quality evidence. 2. ESGE/ESGAR recommend CTC, preferably the same or next day, if colonoscopy is incomplete. The timing depends on an interdisciplinary decision including endoscopic and radiological factors. Strong recommendation, low quality evidence. ESGE/ESGAR suggests that, in centers with expertise in and availability of colon capsule endoscopy (CCE), CCE preferably the same or the next day may be considered if colonoscopy is incomplete. Weak recommendation, low quality evidence. 3. When colonoscopy is contraindicated or not possible, ESGE/ESGAR recommend CTC as an acceptable and equally sensitive alternative for patients with alarm symptoms. Strong recommendation, high quality evidence. Because of lack of direct evidence, ESGE/ESGAR do not recommend CCE in this situation. Very low quality evidence. ESGE/ESGAR recommend CTC as an acceptable alternative to colonoscopy for patients with non-alarm symptoms. Strong recommendation, high quality evidence. In centers with availability, ESGE/ESGAR suggests that CCE may be considered in patients with non-alarm symptoms. Weak recommendation, low quality evidence. 4. Where there is no organized fecal immunochemical test (FIT)-based population colorectal screening program, ESGE/ESGAR recommend CTC as an option for colorectal cancer screening, providing the screenee is adequately informed about test characteristics, benefits, and risks, and depending on local service- and patient-related factors. Strong recommendation, high quality evidence. ESGE/ESGAR do not suggest CCE as a first-line screening test for colorectal cancer. Weak recommendation, low quality evidence. 5. ESGE/ESGAR recommend CTC in the case of a positive fecal occult blood test (FOBT) or FIT with incomplete or unfeasible colonoscopy, within organized population screening programs. Strong recommendation, moderate quality evidence. ESGE/ESGAR also suggest the use of CCE in this setting based on availability. Weak recommendation, moderate quality evidence. 6. ESGE/ESGAR suggest CTC with intravenous contrast medium injection for surveillance after curative-intent resection of colorectal cancer only in patients in whom colonoscopy is contraindicated or unfeasible. Weak recommendation, low quality evidence. There is insufficient evidence to recommend CCE in this setting. Very low quality evidence. 7. ESGE/ESGAR suggest CTC in patients with high risk polyps undergoing surveillance after polypectomy only when colonoscopy is unfeasible. Weak recommendation, low quality evidence. There is insufficient evidence to recommend CCE in post-polypectomy surveillance. Very low quality evidence. 8. ESGE/ESGAR recommend against CTC in patients with acute colonic inflammation and in those who have recently undergone colorectal surgery, pending a multidisciplinary evaluation. Strong recommendation, low quality evidence. 9. ESGE/ESGAR recommend referral for endoscopic polypectomy in patients with at least one polyp ≥6 mm detected at CTC or CCE. Follow-up CTC may be clinically considered for 6–9-mm CTC-detected lesions if patients do not undergo polypectomy because of patient choice, comorbidity, and/or low risk profile for advanced neoplasia. Strong recommendation, moderate quality evidence.Source and scop

Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation

Oxazaphosphorines (Oxaza) represented by cyclophosphamide (CPA) and ifosfamide (IFO) are still the corner stone of several polychemotherapy protocols as they are widely indicated in the treatment of numerous cancer from soft tissue sarcomas to lymphomas and immune-related diseases. However, Oxaza are prodrugs requiring cytochrome (CYP) P450 bioactivation responsible of limiting adverse effects. In the case of IFO, bioactivation leads to a low release of 4-OH-IFO (10%), which generates the active nitrogen mustard displaying DNA cross-links. Associated toxicities of IFO due to acrolein, (urotoxicity) and to chloroacetaldehyde (neuro and nephrotoxicity) have been described. Thus, increasing IFO therapeutic index could be of major interest. To circumvent these toxicities, our team has designed new pre-activated IFO analogs to avoid CYP bioactivation (Skarbek et al J Med Chem 2015). Among these analogues some have the ability to self-assemble as nanoassemblies (NAs), the others can be encapsulated within nano-lipid capsules (NLCs). These new drug delivery systems (DDS) can take advantage of passive targeting, as stealthiness of these DDS can be provided by PEGylation by using Cholesterol-polyethylene glycol or the use of surfactant. These DDS can also be functionalized by appropriate monoclonal antibodies leading to multi stage DDS with active targeting properties. Regarding CPA, it has been shown and described in literature that low doses of CPA enhance the immunity by promoting differentiation of CD4⁺ cell toward Th1. As IFO is isomeric form of CPA, it was assumed that IFO could also have such properties. Studies on immunocompetent MCA205 mouse model, an immunogenic fibrosarcoma mouse model, demonstrate a dose-dependent immunomodulation of IFO towards a modulation of the secretion of IFNy, IL-17A and IL-6 cytokines. The ongoing experiments on mouse model depleted in CD4⁺ T cells and CD8⁺ T cells show the antitumor efficacy of IFO 150mg/kg on these immune cells in tumor regression. Both strategies could lead to the design of nano-immuno-conjugates (NICs) which could benefit of the immunomodulatory effects of X-Oxaza combined to their antiproliferative properties targeted through immune checkpoint antibodies. These new functionalized DDS may provide a useful strategy to give specificity to active drugs used for many years in clinical practice. Both DDS could be grafted with mAbs which could lead to a new family of DDS aiming to combine antiproliferative and immunomodulatory properties for a dual antitumoral action Citation Format: Julia Delahousse, Charles Skarbek, Valentine Gauthier, M Desbois, Emilie Roger, C. Pioche-Durieu, M. Rivard, D. Desmaële, T. Martens, E. LeCam, Jean-Pierre Benoit, P. Couvreur, Nathalie Chaput-Gras, Angelo Paci. Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2195. doi:10.1158/1538-7445.AM2017-219

Gaining Greater Insight into HCV Emergence in HIV-Infected Men Who Have Sex with Men: The HEPAIG Study

OBJECTIVES: The HEPAIG study was conducted to better understand Hepatitis C virus (HCV) transmission among human immuno-deficiency (HIV)-infected men who have sex with men (MSM) and assess incidence of HCV infection among this population in France. METHODS AND RESULTS: Acute HCV infection defined by anti-HCV or HCV ribonucleic acid (RNA) positivity within one year of documented anti-HCV negativity was notified among HIV-infected MSM followed up in HIV/AIDS clinics from a nationwide sampling frame. HIV and HCV infection characteristics, HCV potential exposures and sexual behaviour were collected by the physicians and via self-administered questionnaires. Phylogenetic analysis of the HCV-NS5B region was conducted. HCV incidence was 48/10 000 [95% Confidence Interval (CI):43-54] and 36/10 000 [95% CI: 30-42] in 2006 and 2007, respectively. Among the 80 men enrolled (median age: 40 years), 55% were HIV-diagnosed before 2000, 56% had at least one sexually transmitted infection in the year before HCV diagnosis; 55% were HCV-infected with genotype 4 (15 men in one 4d-cluster), 32.5% with genotype 1 (three 1a-clusters); five men were HCV re-infected; in the six-month preceding HCV diagnosis, 92% reported having casual sexual partners sought online (75.5%) and at sex venues (79%), unprotected anal sex (90%) and fisting (65%); using recreational drugs (62%) and bleeding during sex (55%). CONCLUSIONS: This study emphasizes the role of multiple unprotected sexual practices and recreational drugs use during sex in the HCV emergence in HIV-infected MSM. It becomes essential to adapt prevention strategies and inform HIV-infected MSM with recent acute HCV infection on risk of re-infection and on risk-reduction strategies

Tumor-Associated Macrophages (TAMs) Form an Interconnected Cellular Supportive Network in Anaplastic Thyroid Carcinoma

BACKGROUND: A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC. METHODOLOGY/PRINCIPAL FINDINGS: Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells. CONCLUSION: ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined

Epstein-Barr virus: clinical and epidemiological revisits and genetic basis of oncogenesis

Epstein-Barr virus (EBV) is classified as a member in the order herpesvirales, family herpesviridae, subfamily gammaherpesvirinae and the genus lymphocytovirus. The virus is an exclusively human pathogen and thus also termed as human herpesvirus 4 (HHV4). It was the first oncogenic virus recognized and has been incriminated in the causation of tumors of both lymphatic and epithelial nature. It was reported in some previous studies that 95% of the population worldwide are serologically positive to the virus. Clinically, EBV primary infection is almost silent, persisting as a life-long asymptomatic latent infection in B cells although it may be responsible for a transient clinical syndrome called infectious mononucleosis. Following reactivation of the virus from latency due to immunocompromised status, EBV was found to be associated with several tumors. EBV linked to oncogenesis as detected in lymphoid tumors such as Burkitt's lymphoma (BL), Hodgkin's disease (HD), post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas and oral hairy leukoplakia (OHL). In vitro, EBV many studies have demonstrated its ability to transform B cells into lymphoblastoid cell lines (LCLs). Despite these malignancies showing different clinical and epidemiological patterns when studied, genetic studies have suggested that these EBV- associated transformations were characterized generally by low level of virus gene expression with only the latent virus proteins (LVPs) upregulated in both tumors and LCLs. In this review, we summarize some clinical and epidemiological features of EBV- associated tumors. We also discuss how EBV latent genes may lead to oncogenesis in the different clinical malignancie