Impact of viral hepatitis therapy in multiple myeloma and other monoclonal gammopathies linked to hepatitis B or C viruses.

Subsets of multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS) present with a monoclonal immunoglobulin specific for hepatitis C virus (HCV), thus are presumably HCV-driven, and antiviral treatment can lead to the disappearance of antigen stimulation and improved control of clonal plasma cells. Here we studied the role of hepatitis B virus (HBV) in the pathogenesis of MGUS and MM in 45 HBV-infected patients with monoclonal gammopathy. We analyzed the specificity of recognition of the monoclonal immunoglobulin of these patients and validated the efficacy of antiviral treatment (AVT). For 18 of 45 (40%) HBV-infected patients, the target of the monoclonal immunoglobulin was identified: the most frequent target was HBV (n=11), followed by other infectious pathogens (n=6) and glucosylsphingosine (n=1). Two patients whose monoclonal immunoglobulin targeted HBV (HBx and HBcAg), implying that their gammopathy was HBV-driven, received AVT and the gammopathy did not progress. AVT efficacy was then investigated in a large cohort of HBV-infected MM patients (n=1367) who received or did not receive anti-HBV treatments and compared to a cohort of HCV-infected MM patients (n=1220). AVT significantly improved patient probability of overall survival (P=0.016 for the HBV-positive cohort, P=0.005 for the HCV-positive cohort). Altogether, MGUS and MM disease can be HBV- or HCV-driven in infected patients, and the study demonstrates the importance of AVT in such patients.

Comparison of Monoclonal Gammopathies Linked to Poliovirus or Coxsackievirus vs. Other Infectious Pathogens.

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.

Efficacy of Antiviral Treatment in Hepatitis C Virus (HCV)-Driven Monoclonal Gammopathies Including Myeloma.

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.

Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1ß and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms.

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-1ß, IL-1Rα, 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-1ß, 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-1ß 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.

Analysis of the Targets and Glycosylation of Monoclonal IgAs From MGUS and Myeloma Patients.

Previous studies showed that monoclonal immunoglobulins G (IgGs) of "monoclonal gammopathy of undetermined significance" (MGUS) and myeloma were hyposialylated, thus presumably pro-inflammatory, and for about half of patients, the target of the monoclonal IgG was either a virus-Epstein-Barr virus (EBV), other herpes viruses, hepatitis C virus (HCV)-or a glucolipid, lysoglucosylceramide (LGL1), suggesting antigen-driven disease in these patients. In the present study, we show that monoclonal IgAs share these characteristics. We collected 35 sera of patients with a monoclonal IgA (6 MGUS, 29 myeloma), and we were able to purify 25 of the 35 monoclonal IgAs (6 MGUS, 19 myeloma). Monoclonal IgAs from MGUS and myeloma patients were significantly less sialylated than IgAs from healthy volunteers. When purified monoclonal IgAs were tested against infectious pathogens and LGL1, five myeloma patients had a monoclonal IgA that specifically recognized viral proteins: the core protein of HCV in one case, EBV nuclear antigen 1 (EBNA-1) in four cases (21.1% of IgA myeloma). Monoclonal IgAs from three myeloma patients reacted against LGL1. In summary, monoclonal IgAs are hyposialylated and as described for IgG myeloma, significant subsets (8/19, or 42%) of patients with IgA myeloma may have viral or self (LGL1) antigen-driven disease.

Characteristics of MGUS and Multiple Myeloma According to the Target of Monoclonal Immunoglobulins, Glucosylsphingosine, or Epstein-Barr Virus EBNA-1.

: Chronic stimulation by infectious or self-antigens initiates subsets of monoclonal gammopathies of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM). Recently, glucosylsphingosine (GlcSph) was reported to be the target of one third of monoclonal immunoglobulins (Igs). In this study of 233 patients (137 MGUS, 6 SMM, 90 MM), we analyzed the GlcSph-reactivity of monoclonal Igs and non-clonal Igs. The presence of GlcSph-reactive Igs in serum was unexpectedly frequent, detected for 103/233 (44.2%) patients. However, GlcSph was targeted by the patient's monoclonal Ig for only 37 patients (15.9%); for other patients (44 MGUS, 22 MM), the GlcSph-reactive Igs were non-clonal. Then, the characteristics of patients were examined: compared to MM with an Epstein-Barr virus EBNA-1-reactive monoclonal Ig, MM patients with a GlcSph-reactive monoclonal Ig had a mild presentation. The inflammation profiles of patients were similar except for moderately elevated levels of 4 cytokines for patients with GlcSph-reactive Igs. In summary, our study highlights the importance of analyzing clonal Igs separately from non-clonal Igs and shows that, if autoimmune responses to GlcSph are frequent in MGUS/SMM and MM, GlcSph presumably represents the initial pathogenic event for ~16% cases. Importantly, GlcSph-initiated MM appears to be a mild form of MM disease.

Pro-inflammatory State in Monoclonal Gammopathy of Undetermined Significance and in Multiple Myeloma Is Characterized by Low Sialylation of Pathogen-Specific and Other Monoclonal Immunoglobulins.

Multiple myeloma (MM) and its pre-cancerous stage monoclonal gammopathy of undetermined significance (MGUS) allow to study immune responses and the chronology of inflammation in the context of blood malignancies. Both diseases are characterized by the production of a monoclonal immunoglobulin (mc Ig) which for subsets of MGUS and MM patients targets pathogens known to cause latent infection, a major cause of inflammation. Inflammation may influence the structure of both polyclonal (pc) Ig and mc Ig produced by malignant plasma cells via the sialylation of Ig Fc fragment. Here, we characterized the sialylation of purified mc and pc IgGs from 148 MGUS and MM patients, in comparison to pc IgGs from 46 healthy volunteers. The inflammatory state of patients was assessed by the quantification in serum of 40 inflammation-linked cytokines, using Luminex technology. While pc IgGs from MGUS and MM patients showed heterogeneity in sialylation level, mc IgGs from both MGUS and MM patients exhibited a very low level of sialylation. Furthermore, mc IgGs from MM patients were less sialylated than mc IgGs from MGUS patients (p < 0.01), and mc IgGs found to target an infectious pathogen showed a lower level of sialylation than mc IgGs of undetermined specificity (p = 0.048). Regarding inflammation, 14 cytokines were similarly elevated with a p value < 0.0001 in MGUS and in MM compared to healthy controls. MM differed from MGUS by higher levels of HGF, IL-11, RANTES and SDF-1-α (p < 0.05). MGUS and MM patients presenting with hyposialylated pc IgGs had significantly higher levels of HGF, IL-6, tumor necrosis factor-α, TGF-ß1, IL-17, and IL-33 compared to patients with hyper-sialylated pc IgGs (p < 0.05). In MGUS and in MM, the degree of sialylation of mc and pc IgGs and the levels of four cytokines important for the anti-microbial response were correlated, either positively (IFN-α2, IL-13) or negatively (IL-17, IL-33). Thus in MGUS as in MM, hyposialylation of mc IgGs is concomitant with increased levels of cytokines that play a major role in inflammation and anti-microbial response, which implies that infection, inflammation, and abnormal immune response contribute to the pathogenesis of MGUS and MM.

Value of CT enteroclysis in suspected small-bowel carcinoid tumors.

OBJECTIVE: 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. SUBJECTS AND METHODS: 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). RESULTS: 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. CONCLUSION: CT enteroclysis should be considered an excellent tool for the diagnosis of the carcinoid tumor before any surgical procedures.

Liver steatosis quantification using magnetic resonance imaging: a prospective comparative study with liver biopsy.

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 T1-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.

Initial management of extensive mesenteric venous thrombosis: retrospective study of nine cases.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Long-term outcome of percutaneous transhepatic therapy for benign bilioenteric anastomotic strictures.

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.

Multiplanar reconstruction: a new method for the diagnosis of tracheobronchial rupture?

OBJECTIVE: To compare multiplanar reconstruction with operative techniques (bronchoscopy, surgery and/or autopsy) for the diagnosis of tracheobronchial rupture. DESIGN: Prospective, observational study. SETTING: Surgical intensive care unit. PATIENTS AND PARTICIPANTS: Tracheobronchial rupture was suspected on clinical grounds and from radiological findings. INTERVENTIONS: 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. MEASUREMENTS AND RESULTS: 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. CONCLUSIONS: 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. DESCRIPTOR: Trauma.