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International audience; Multiple myeloma (MM) remains an incurable plasma cell malignancy. While its origin is enigmatic, an association with infectious pathogens including hepatitis C virus (HCV) has been suggested. Here we report nine patients with monoclonal gammopathy of undetermined significance (MGUS) or MM with previous HCV infection, six of whom received antiviral treatment. We studied the evolution of the gammopathy disease, according to anti-HCV treatment and antigen specificity of purified monoclonal immunoglobulin, determined using the INNO LIA™ HCV Score assay, dot-blot assays, and a multiplex infectious antigen microarray. The monoclonal immunoglobulin from 6/9 patients reacted against HCV. Four of these patients received antiviral treatment and had a better evolution than untreated patients. Following antiviral treatment, one patient with MM in third relapse achieved complete remission with minimal residual disease negativity. For two patients who did not receive antiviral treatment, disease progressed. For the two patients whose monoclonal immunoglobulin did not react against HCV, antiviral treatment was not effective for MGUS or MM disease. Our results suggest a causal relationship between HCV infection and MGUS and MM progression. When HCV was eliminated, chronic antigen-stimulation disappeared, allowing control of clonal plasma cells. This opens new possibilities of treatment for MGUS and myeloma.

International audience; Chronic stimulation by infectious pathogens or self-antigen glucosylsphingosine (GlcSph) can lead to monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Novel assays such as the multiplex infectious antigen microarray (MIAA) and GlcSph assays, permit identification of targets for >60% purified monoclonal immunoglobulins (Igs). Searching for additional targets, we selected 28 purified monoclonal Igs whose antigen was not represented on the MIAA and GlcSph assays; their specificity of recognition was then analyzed using microarrays consisting of 3760 B-cell epitopes from 196 pathogens. The peptide sequences PALTAVETG and PALTAAETG of the VP1 coat proteins of human poliovirus 1/3 and coxsackievirus B1/B3, respectively, were specifically recognized by 6/28 monoclonal Igs. Re-analysis of patient cohorts showed that purified monoclonal Igs from 10/155 MGUS/SM (6.5%) and 3/147 MM (2.0%) bound to the PALTAVETG or PALTAAETG epitopes. Altogether, PALTAV/AETG-initiated MGUS are not rare and few seem to evolve toward myeloma.

Inflammatory cytokines play a major role in myeloproliferative neoplasms (MPNs) as regulators of the MPN clone and as mediators of clinical symptoms and complications. Firstly, we investigated the effect of JAK2V617F on 42 molecules linked to inflammation. For JAK2V617F-mutated patients, the JAK2V617F allele burden (%JAK2V617F) correlated with the levels of IL-1&beta, IL-1R&alpha, IP-10 and leptin in polycythemia vera (PV), and with IL-33 in ET, for all other molecules, no correlation was found. Cytokine production was also studied in the human megakaryocytic cell line UT-7. Wild-type UT-7 cells secreted 27/42 cytokines measured. UT-7 clones expressing 50% or 75% JAK2V617F were generated, in which the production of IL-1&beta, IP-10 and RANTES was increased, other cytokines were not affected. Secondly, we searched for causes of chronic inflammation in MPNs other than driver mutations. Since antigen-driven selection is increasingly implicated in the pathogenesis of blood malignancies, we investigated whether proinflammatory glucosylsphingosine (GlcSph) may play a role in MPNs. We report that 20% (15/75) of MPN patients presented with anti-GlcSph IgGs, distinguished by elevated levels of 11 cytokines. In summary, only IL-1&beta, and IP-10 were linked to JAK2V617F both in patients and in UT-7 cells, other inflammation-linked cytokines in excess in MPNs were not. For subsets of MPN patients, a possible cause of inflammation may be auto-immunity against glucolipids.

Background: Multiple myeloma remains an incurable plasma cell malignancy. While its origin is enigmatic, an association with infectious pathogens including hepatitis C virus (HCV) has been suggested. Methods: We studied thirteen patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma with previous HCV infection. Viral load was quantified using the VERIS MDx system. The antigen specificity of purified monoclonal immunoglobulins was determined using the INNO-LIA HCV Score, dot-blot assays, and a multiplex infectious-antigen microarray. Findings: The target of the purified monoclonal immunoglobulin was identified for 8/13 patients. The monoclonal immunoglobulin from 6/8 patients reacted against HCV. Four of the patients received antiviral treatment and had a better evolution than untreated patients. Following antiviral treatment, one patient with multiple myeloma in third relapse achieved complete remission with minimal residual disease negativity, as assessed by next generation multiparameter flow cytometry. Two patients did not receive antiviral treatment and progressed. For the two additional patients whose monoclonal immunoglobulin did not react against HCV, antiviral treatment was not effective for MGUS or multiple myeloma disease. Interpretation: Our results suggest a causal relationship between HCV infection and MGUS and multiple myeloma progression. When HCV is eliminated, chronic antigen-stimulation disappears, allowing control of clonal plasma cells. This opens new possibilities of treatment for MGUS and multiple myeloma. Funding Statement: This work was supported by grants to S.H. from the Ligue Nationale contre le Cancer (Comites Departementaux 44, 56, 29, 85, 35) and International Myeloma Foundation (IMF) (Brian D. Novis senior grant). We acknowledge of Instituto de Investigacion Hospital 12 de Octubre (i+12), CIBERONC, AECC (Accelerator Award), and the CRIS foundation for their help. M.L. had a postdoctoral fellowship from the Spanish Ministry of Economy and Competitiveness (FPDI-2013-16409) and a grant from the Spanish Society of Hematology Declaration of Interests: All authors declare no conflicts of interest. Ethics Approval Statement: The study was approved by our Institutional Review Board and the patients provided written informed consent in accordance with the Declaration of Helsinki.

International audience; Background:Iodinated and gadolinium-based contrast media (ICM; GBCM) induce immediate hypersensitivity (IH) reactions. Differentiating allergic from non-allergic IH is crucial; allergy contraindicates the culprit agent for life. We studied frequency of allergic IH among ICM or GBCM reactors.Methods:Patients were recruited in 31 hospitals between 2005 and 2009. Clinical symptoms, plasma histamine and tryptase concentrations and skin tests were recorded. Allergic IH was diagnosed by intradermal tests (IDT) with the culprit CM diluted 1:10, "potentially allergic" IH by positive IDT with pure CM, and non-allergic IH by negative IDT.Findings:Among 245 skin-tested patients (ICM = 209; GBCM = 36), allergic IH to ICM was identified in 41 (19.6%) and to GBCM in 10 (27.8%). Skin cross-reactivity was observed in 11 patients with ICM (26.8%) and 5 with GBCM (50%). Allergy frequency increased with clinical severity and histamine and tryptase concentrations (p 50% of life-threatening ones. GBCM and ICM triggered comparable IH reactions in frequency and severity. Cross-reactivity was frequent, especially for GBCM. We propose considering skin testing with pure contrast agent, as it is more sensitive than the usual 1:10 dilution criteria.

INTRODUCTION: Recently, new understanding of monoclonal gammopathy pathogenesis highlighted possible disease initiation by viral infection in subsets of patients, notably by hepatitis C virus (HCV). If the infectious pathogen targeted by the monoclonal Ig could be eliminated at the monoclonal gammopathy of undetermined significance (MGUS) stage, chronic antigen-stimulation could disappear, leading in turn to the disappearance of the monoclonal Ig. Here we report a series of patients with monoclonal gammopathy and HCV infection, whose disease prognosis clearly improved, even reached complete remission, after antiviral treatment. METHODS: Nine patients diagnosed with MGUS (n=6) or multiple myeloma (MM) (n=3) after HCV infection were included in the study and classified into two groups: patients who received antiviral treatment, and patients who did not receive anti-viral treatment. Disease status was monitored by the quantification of the monoclonal immunoglobulin (mc Ig) level. The HCV burden was determined by RT-qPCR. Each patient's mc Ig was isolated from polyclonal immunoglobulins by agarose gel electrophoresis and mc Ig purity was evaluated by isoelectric focusing. The multiplex infectious antigen microarray (MIAA) was used to analyze the reactivity of serum immunoglobulins and of monoclonal Ig against commercially available antigens and/or lysates from different microorganisms. The INNO-LIA™ HCV Score assay (Fujirebio) was used to analyze the reactivity of monoclonal Ig to HCV proteins. RESULTS: Regarding patients treated with antiviral drugs (4 MGUS, 2 MM), mc Ig levels in serum decreased after antiviral treatment. MGUS patients remained in a stable status without disease progression. After antiviral treatment, one MM patient who was in third relapse achieved complete remission with minimal residual disease negativity. As expected, the HCV load decreased after antiviral therapy to undetectable levels. Serum samples from patients were reactive against antigens of various viruses and other microorganisms, but analysis of the specificity of recognition of the purified mc Ig of each patient revealed that it targeted HCV, either the core protein (C1, C2), NS3, or NS4. In contrast, for patients who did not receive antiviral treatment (2 MGUS, 1 MM), MGUS and MM disease progressed and the mc Ig level remained stable or increased. Serum samples from these patients were reactive against various viruses and other microorganisms, but their mc Ig did not recognize HCV proteins. CONCLUSION: In this study of monoclonal gammopathies where the mc Ig targeted HCV, successful HCV eradication with antivirals resulted in improvement of MGUS and MM disease as well as of hepatitis C. Our findings suggest that for HCV-positive individuals who were infected before being diagnosed with MGUS or MM, a causal relationship exists between HCV infection and the development of MGUS and MM, and both MGUS and MM patients infected with HCV may benefit from early anti-HCV therapy. Disclosures No relevant conflicts of interest to declare.

* A.R. and M.L. have contributed equally. INTRODUCTION: Despite great advances in knowledge and treatment in the last decade, multiple myeloma (MM) remains an incurable disease. Several studies suggest its association with infectious pathogens, such as hepatitis C virus (HCV) and Epstein Barr virus (EBV). Here we report on the case of a female MM patient in fourth relapse (after VTD treatment + ASCT+ Lenalodomide maintenance and experimental NK therapy + Lenalidomide and lastly Bendamustine), who achieved stable complete response (CR) once her HCV infection was successfully treated, thus establishing a probable relationship between HCV infection and MM in this patient. METHODS: Serum samples from the patient were analyzed before and after antiviral treatment (Sofusbuvir + Ledipasvir). The HCV burden was determined by RT-qPCR. Additionally, viral loads of EBV and Cytomegalovirus were established by qPCR.The number of tumor plasma clones was determined in bone marrow samples by NGS using the Ion Proton sequencer and a depth of 2000 readings/nucleotide. Monoclonal immunoglobulins (mc Ig) were separated from polyclonal Ig by agarose gel electrophoresis and elution. Mc Ig purity was evaluated by isoelectric focusing and immunodetection with anti-IgG antibodies. Their reactivity to different microbial antigens was determined by means of the multiplex infectious-antigen microarray (MIAA) assay and using the commercial kit INNO-LIA HCV score (Fujirebio). RESULTS: The patient, age 66, presented with ISS IIA stage MM (56.7 g/L mc IgG, 2.7 g/L free lambda chains, 2.9 mg/L b2-microglobulin, 90% plasma cells in the bone marrow, without genetic alterations, and osteolytic lesions). HCV infection, causing hepatic toxicity, was discovered in this patient before MM disease. The patient was in third relapse of MM treatment when she received anti-HCV treatment. After antiviral therapy, the HCV load in the patient's serum decreased to undetectable levels (Fig. 1a). Simultaneously, the patient achieved CR of MM, with minimal residual disease (MRD) negativity, as assessed by multiparameter flow cytometry (MFC). NGS revealed the existence of at least one plasmacytic clone, which became MRD negative after anti-HCV treatment (Fig. 1b). Before and after anti-HCV treatment, the patient's serum samples were reactive against antigens of various viruses and other microorganisms (Fig. 1c). Agarose gel electrophoresis of pre-HCV treatment samples showed one band of mc IgG, which disappeared after anti-HCV treatment (Fig. 1d). The patient's mc IgG was purified (Fig. 1e) and analysis of its specificity of recognition revealed that it targeted the HCV core protein (Fig. 1f). Three years have now passed after HCV treatment, and the patient remains in stable CR of MM. CONCLUSION: In this case of refractory MM where the patient's mc IgG targeted HCV, successful HCV eradication with antivirals Sofosbuvir and Ledipasvir resulted in persistent complete remission of MM as well as of hepatitis C. These results suggest that for HCV-positive individuals, a causal relationship exists between HCV infection and the development of MM, and that MM patients infected with HCV would benefit from early anti-HCV therapy. Disclosures Martinez Lopez: Celgene: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

The development of mesenteric venous thrombosis (MVT) does not necessarily require surgical intervention. The aim of this study was to assess the efficacy of avoiding early operative intervention, which can lead to significant sacrifice of the small bowel. Patients with MVT were identified using the inpatient registry for the years between 2003 and 2007. Each patient’s past medical history, history of prior deep venous thrombosis or hypercoagulable state, clinical and biologic presentation, and computed tomography (CT) results were analyzed. The proportion of ischemic bowel observed on the CT scans was compared with the length of the bowel resected. Nine patients were admitted for extensive MVT during the time period evaluated (six men, three women). All CT scans demonstrated signs of severe bowel ischemia, with a mean ischemic bowel proportion of 21% (range 5–45%). Four patients received medical management alone. Five patients underwent surgery. The mean admission time for these patients prior to the operation was 14.8 days (6–36 days). Surgery was required only in cases of intestinal perforation. The mean length of the bowel resections was 33 cm (20–45 cm). At 6 months after admission, none of the patients required parenteral nutrition. The mean follow-up evaluation period was 27 months (15–38 months). One patient died secondary to amyotrophic lateral sclerosis during the follow-up. Initial nonsurgical management comprised of inpatient observation on a surgical ward along with systemic anticoagulation must be considered an alternative treatment strategy for MVT. This strategy delays surgery and therefore avoids short bowel syndrome.

To compare multiplanar reconstruction with operative techniques (bronchoscopy, surgery and/or autopsy) for the diagnosis of tracheobronchial rupture. Prospective, observational study. Surgical intensive care unit. Tracheobronchial rupture was suspected on clinical grounds and from radiological findings. An initial helical computed tomography scan was performed on all patients meeting the inclusion criteria, and operative techniques were then performed. Multiplanar reconstructions were reformatted and reviewed by two independent radiologists. Twenty-four consecutive patients met the inclusion criteria. Tracheobronchial rupture was diagnosed in 13 patients by at least one operative technique. Multiplanar reconstructions were positive in 15 patients. The diagnostic sensitivity and specificity of multiplanar reconstructions were 100% (95%CI, 85–100) and 82% (95%CI, 64–82), respectively. The positive and negative predictive values were 87% (95%CI, 74–87) and 100% (95%CI, 78–100), respectively. For tracheobronchial rupture, the positive and negative likelihood ratios were 5.5 (95%CI, 2.35–5.5) and 0 (95%CI, 0–0.24), respectively. The Kappa coefficients were 0.83 (95%CI, 0.6–1.06) for agreement between operative techniques and multiplanar reconstruction, and 0.91 (95%CI, 0.59–0.91) for agreement between the two radiologists. Multiplanar reconstruction appears to be a sensitive technique for the identification of tracheobronchial rupture because of its excellent negative likelihood ratio. In clinical practice, negative multiplanar reconstruction can exclude a diagnosis of tracheobronchial rupture, making bronchoscopy unnecessary. When multiplanar reconstruction is positive, tracheobronchial rupture should be confirmed by bronchoscopy. Trauma.

The purpose of this study was to evaluate the value of CT enteroclysis in depicting small-bowel carcinoid tumors in symptomatic patients with surgical, histologic, or clinical follow-up findings as a reference standard.At our institution, 44 patients with symptoms of suspected gastrointestinal carcinoid tumors underwent CT enteroclysis. Clinical symptoms were as follows: carcinoid syndrome (n = 3), abdominal pain with diarrhea (n = 24), hypervascular liver metastases (n = 7), subileus condition (n = 1), hypervascular peritoneal lesion (n = 3), abnormal ileal stenosis on optical colonoscopy (n = 3), and follow-up extraintestinal carcinoid lesion (n = 3). Positive CT enteroclysis findings were compared with pathology results after surgical procedures (n = 19). Negative examinations were compared with surgery results (n = 3) or clinical follow-up (n = 22).CT enteroclysis findings were positive in 19 patients and negative in 25 patients. The sizes of the carcinoid tumors identified were 5-30 mm in axial diameter. These tumors were depicted as focal nodular lesions located in the small-bowel wall or as intraluminal polypoid masses with marked enhancement. Twenty-two patients underwent only clinical follow-up, with a mean clinical follow-up time of 20 months. The overall sensitivity and specificity of CT enteroclysis in identifying patients with small-bowel carcinoid tumors were 100% and 96.2%, respectively. The negative predictive value of CT enteroclysis was 100% and the positive predictive value, 94.7%. Pathologic findings confirmed small-bowel carcinoid tumors in 18 patients.CT enteroclysis should be considered an excellent tool for the diagnosis of the carcinoid tumor before any surgical procedures.

Background and Aims: To prospectively determine the accuracy of liver fat quantification with magnetic resonance imaging (MRI). Patients and Methods: The population consisted of 40 patients (mean age, 52.5 years; range, 23―78 years). The same day, all patients underwent MRI and ultrasonography-guided liver biopsy. The histological evaluation of steatosis was performed by an experienced liver pathologist blinded to the MRI results. On Tl-weighted in- and opposed-phase images, one radiologist, experienced in abdominal imaging, blinded to the clinical and pathological results, recorded signal intensity (SI) by mean regions of interest placed at same locations in both phases. Fat-water ratio was obtained by dividing SI of liver in opposed-phase sequence by SI of liver in in-phase sequence. The fat-water ratio and the histological grade of steatosis were compared by linear regression. Receiver operating characteristic curve was used to define the sensitivity and specificity of fat-water ratio as a diagnostic tool for evaluation of steatosis. Results: Diagnoses were nonalcoholic fatty liver disease (n = 25), alcoholic liver disease (n = 10), cholangiopathy (n = 2), and autoimmune hepatitis (n = 3). Fatty liver infiltration was present in 80% of patients. The mean (SD) percentage of fatty hepatocytes was 38.7% (29.2). Fat-water ratio and steatosis grade were highly correlated (r = 0.852, P < 0.0001). Sensitivity and specificity of fat-water ratio to detect fatty infiltration greater than 20% were 96% and 93%, respectively. Conclusions: This prospective study demonstrates that MRI can be proposed as a noninvasive method to screen and quantify liver steatosis.

Purpose To evaluate the long-term outcomes of a percutaneous transhepatic approach in benign bilioenteric anastomoses with calibration of the stenosis to 15 F and extended internal/external drainage. Materials and Methods Between February 2000 and May 2007, the efficacy of this percutaneous transhepatic procedure was retrospectively studied in 39 patients with benign postoperative bilioenteric anastomotic strictures. The main purpose of the protocol was to repair the anastomosis by calibration of the stenosis to 15 F with a silicone drain and perform internal/external drainage for at least 1 year. The follow-up period ranged from 12 to 65 months (mean, 34.4 months), and outcomes were classified according to the patient's clinical symptoms and laboratory parameters and the need for further interventions. Results The procedure was successful in 38 of 39 patients. Four patients were lost to follow-up during or after drainage. The duration of drainage (41 internal catheters in 34 patients) ranged from 126 days to 488 days (mean, 346 d). Twenty-seven patients had positive outcomes during the mean follow-up of 34 months, and six patients had negative outcomes. The bile duct patency probability according to the Kaplan-Meier method was and 70.6% at 34 months after drain removal. Conclusions Percutaneous treatment of benign biliary strictures with calibrated stent implantation and extended drainage has good long-term results and may be an effective alternative to surgery. Advantages over surgery are its minimal invasiveness and reduced risk of complications.