Relevance of blood tumor markers in inpatients with significant involuntary weight loss and elevated levels of inflammation biomarkers.

PURPOSE: To assess the diagnostic performance of a panel of standard tumor markers (TMs) in patients hospitalized with significant involuntary weight loss (IWL) and elevated levels of inflammation biomarkers, and a combination of the TM panel and the finding of the computed tomography (CT) scan. METHODS: We conducted a retrospective study in the internal medicine department at Amiens-Picardie University Medical Center (Amiens, France) between January 1st, 2015, and November 1st, 2021. The inclusion criteria were age 18 or over, significant IWL (≥ 5 kg over 6 months), elevated inflammation biomarkers (e.g. C-reactive protein), and assay data on two or more standard TMs (carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19 - 9, CA 15 - 3, CA 125, neuron-specific enolase (NSE), alpha-fetoprotein (AFP), calcitonin, and prostate-specific antigen (PSA)). The result of each TM assay was interpreted qualitatively (as positive or negative), according to our central laboratory's usual thresholds. RESULTS: Cancer was diagnosed in 50 (37.0%) of the 135 patients included. Positivity for one or more TMs had a positive predictive value (PPV) of 0.55 [0.43-0.66], and a negative predictive value (NPV) of 0.84 [0.75-0.93] for cancer diagnosis. When combined with the presence of suspicious CT findings (e.g. a mass, enlarged lymph nodes and/or effusion), positivity for one or more TMs had a PPV of 0.92 [0.08-0.30]. In the absence of suspicious CT findings, a fully negative TM panel had an NPV of 0.96 [0.89-1.00]. CONCLUSION: A negative TM panel argues against the presence of a cancer, especially in the absence of suspicious CT findings.

Clinical, Radiologic, and Immunologic Features of Patients With CTLA4 Deficiency With Neurologic Involvement.

OBJECTIVES: CTLA4 deficiency (CTLA4d) is a disease with multisystem autoimmune features, including neurologic manifestations. We aimed to describe neurologic involvement in these patients. METHODS: We performed a cross-sectional observational study using the French Reference Centre for Primary Immunodeficiencies (CEREDIH) registry plus a surveillance in national society networks. Participants with confirmed CTLA4d and neurologic involvement were included. Clinical, laboratory, and radiologic features were collected, as well as treatments. Available MRI was double-reviewed. RESULTS: Among 70 patients with CTLA4d, 13 patients (21%) had neurologic involvement. Neurologic symptoms began at a median age of 18 [15-45] years, mostly occurring after systemic manifestations (median delay: 8.5 [4.5-10.5] years). Main symptoms included headaches, focal deficit (54% each), and seizures (38%). MRI detected at least 1 large contrast-enhancing lesion in 8 patients. Lesions reminiscent of multiple sclerosis lesions were found in 6 patients. Cerebellar (6 patients) and large spinal cord lesions (3 patients) were common. Ten patients were treated with abatacept, of whom 9 (90%) showed good clinical and radiologic response. DISCUSSION: Neurologic involvement is common among patients with CTLA4d. Despite its rarity, and considering the suspected efficacy of abatacept, neurologists should be aware of the characteristics of CTLA4d neurologic involvement.

Value of Positron Emission Tomography Coupled With Computed Tomography for the Diagnosis of Inflammatory Syndrome of Unknown Origin in an Internal Medicine Department.

Objective: To evaluate the usefulness of positron emission tomography (PET) coupled with computed tomography (CT) in the diagnostic workup for inflammatory syndrome of undetermined origin (IUO) and to determine the diagnostic delay in an internal medicine department. Patients and methods: We retrospectively studied a cohort of patients for whom a PET/CT scan had been prescribed in an indication of IUO in an internal medicine department (Amiens University Medical Center, Amiens, France) between October 2004 and April 2017. The patients were grouped according to the PET/CT findings: very useful (enabling an immediate diagnosis), useful, not useful, and misleading. Results: We analyzed 144 patients. The median (interquartile range) age was 67.7 years (55.8-75.8 years). The final diagnosis was an infectious disease in 19 patients (13.2%), cancer in 23 (16%), inflammatory disease in 48 (33%), and miscellaneous diseases in 12 (8.3%). No diagnosis was made in 29.2% of the cases; half of the remaining had a spontaneously favorable outcome. Fever was observed in 63 patients (43%). Positron emission tomography coupled with CT was determined to be very useful in 19 patients (13.2%), useful in 37 (25.7%), not useful in 63 (43.7%), and misleading in 25 (17.4%). The median diagnostic delay (ie, the time interval between the first admission and a confirmed diagnosis) was significantly shorter in the useful (71 days [38-170 days]) and very useful (55 days [13-79 days]) groups than that in the not useful group (175 days [51-390 days]; P<.001). The median time interval between the PET/CT scan and the diagnosis was twice as long in the not useful group than that in the pooled misleading, useful, or very useful groups (P=.03). In a univariate analysis, the poor overall condition (P=.007) and the absence of fever (P=.005) were predictive of usefulness of PET/CT. Conclusion: Positron emission tomography coupled with CT seems to be useful in the diagnosis of IUO and might shorten the diagnostic delay.

Cutaneous involvement in relapsed multiple myeloma.

Cutaneous involvement in multiple myeloma with extramedullary disease is rare. We report the case of a refractory multiple myeloma patient who developed a cutaneous lesion. Histopathology revealed dermal immature plasma cell infiltrate with a lack of CD138 expression. This cutaneous location was associated with an aggressive clinical course and short survival.

Prognostic factors of Pasteurella infections: a single-center retrospective cohort study over a 14-year period (2005-2018).

BACKGROUND: Pasteurella spp. can lead to fatal infections in humans. OBJECTIVE: To assess prognostic factors of invasive pasteurellosis. METHODS: We conducted a single retrospective cohort study of local versus invasive Pasteurella infections from January 1, 2005, to December 31, 2018, in the Amiens-Picardie University Hospital, France. RESULTS: Forty-five (20.9%) invasive pasteurellosis and 22 (10.2%) complicated local infections were reported among a total of 215 Pasteurella infections. The mortality rate among invasive infections was 22.2% (10/ 45) whereas no death was recorded in local infections group. Non-drug-induced prothrombin time test <70% of standard and platelet counts <100,000/mm3 were more frequent in non-survivors than in survivors (p=0.005 and p=0.019) in univariate analyses. A history of neoplasia (adjusted OR=13.62, p=0.020), an evidence of bacteremia (adjusted OR=20.68, p=0.025), and hemoglobin level <10 g/dL (adjusted OR=17.80, p=0.028) were identified as poor prognostic factors in multivariate analyses. CONCLUSION: Invasive pasteurellosis appears as a serious disease in vulnerable patients, particularly if bacteremia and/or coagulopathies occur.

Analysis of Mesencephalic Astrocyte-derived Neurotrophic Factor in Multiple Myeloma.

BACKGROUND/AIM: Multiple myeloma (MM) is characterized by high production of immunoglobulins resulting in a constant source of endoplasmic reticulum (ER)-stress. Mesencephalic astrocyte-derived neurotrophic factor (MANF) was identified as a possible circulating biomarker that could help in monitoring ER-stress mediated diseases. MATERIALS AND METHODS: To assess the relevance of MANF in MM, we performed in silico and in vitro analysis in malignant cell lines including the myeloma cell line RPMI 8226. Serum MANF concentration was compared between healthy subjects (n=60), patients with MM (n=68), or those with monoclonal gammopathy of undetermined significance (MGUS) (n=73). RESULTS: MANF mRNA expression was upregulated in the RPMI 8226 cell line, and higher secretion of MANF was measured in RPMI 8226 supernatant. Serum MANF levels were not significantly different between MM or MGUS patients and those in age- and sex-matched healthy controls. CONCLUSION: MANF was not validated as a biomarker of interest in MM patients. Its potential implication in myeloma pathogenesis should be investigated.

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.

Coronavirus-induced autoimmunity.

The pandemic of Coronavirus disease 2019 (COVID-19), caused by a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spotlighted the link between viral infection and autoimmunity. In this review, we focus on coronavirus-induced autoimmunity based on evidence from experimental animal models, SARS-CoV infection with in vitro studies of molecular mimicry and COVID-19 with several clinical reports of autoimmune manifestations of this disease. Further studies will be needed to better characterize the role of SARS-CoV-2 in the development of autoimmunity.

A pan-cancer analysis of the human tumor coagulome and its link to the tumor immune microenvironment.

OBJECTIVE: Solid tumors often establish a procoagulable state that can lead to venous thromboembolism (VTE). Although some of the key genes involved in this process are known, no previous study has compared the "coagulome", i.e., the expression of coagulation/fibrinolysis genes, across different primary tumor types. It is also unclear whether the coagulome is associated with specific characteristics of the tumor microenvironment (TME). We aimed to address this question. METHODS: We analyzed the expression of the genes F3, PLAU, PLAT, PLAUR, SERPINB2, and SERPINE1 in 32 cancer types using data from The Cancer Genome Atlas (TCGA) and other freely available resources. RESULTS: We identified specific expression patterns of procoagulant and fibrinolytic genes. The expression of the Tissue Factor (F3) was found to be tumor type dependent, with the highest expression in glioblastoma (GBM), a highly procoagulable tumor type. Conversely, high expression of the fibrinolysis gene cluster PLAU, PLAUR, SERPINE1 was consistently linked to the characteristics of the TME (monocytic infiltration) and high expression of important checkpoints of the immune response, such as PD-L2 and CD276/B7-H3. CONCLUSION: These tumor-specific patterns of expression might partially explain the differences in VTE risk among tumor types. We propose that biomarkers of coagulation fibrinolysis might provide valuable information about the TME in cancer patients.

Obstetrical outcome and treatments in seronegative primary APS: data from European retrospective study.

OBJECTIVE: To compare characteristics, pregnancies and treatments during pregnancies of seronegative and seropositive antiphospholipid syndrome (APS), to analyse factors associated with obstetrical outcome. PATIENTS AND METHODS: Inclusion criteria were: (1) thrombotic and/or obstetrical APS (Sydney criteria); (2) absence of conventional antiphospholipid antibodies (APL); (3) at least one persistent non-conventional APL among IgA anticardiolipin antibodies, IgA anti-B2GPI, anti-vimentin G/M, anti-annexin V G/M, anti-phosphatidylethanolamine G/M and anti-phosphatidylserine/prothrombin G/M antibodies. The exclusion criteria were: (1) systemic lupus erythematosus ( SLE) or SLE-like disease; and (2) other connective tissue disease. RESULTS: A total of 187 women (mean 33±5 years) with seronegative APS were included from 14 centres in Austria, Spain, Italy, Slovenia and France and compared with 285 patients with seropositive APS. Seronegative APS has more obstetrical rather than thrombotic phenotypes, with only 6% of venous thrombosis in comparison to seropositive APS. Cumulative incidence of adverse obstetrical events was similar in seronegative and seropositive APS patients, although higher rates of intrauterine deaths (15% vs 5%; p=0.03), of preeclampsia (7% vs 16%, p=0.048) and lower live birth term (36±3 vs 38±3 weeks of gestation; p=0.04) were noted in seropositive APS. The cumulative incidence of adverse obstetrical events was significantly improved in treated versus untreated seronegative APS (log rank<0.05), whereas there was no difference between patients who received aspirin or aspirin-low-molecular weighted heparin combination. CONCLUSION: Several non-criteria APL can be detected in patients with clinical APS features without any conventional APL, with various rates. The detection of non-criteria APL and thus the diagnosis of seronegative APS could discuss the therapeutic management similar to seropositive APS, but well-designed controlled studies are necessary.

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.

Acute Airway Obstruction and Cardiopulmonary Arrest due to Tracheomalacia Caused by Megaesophagus Compression Secondary to Achalasia.

We report the case of an 80-year-old woman who presented one episode of cardiopulmonary arrest and two episodes of acute airway obstruction. We found in this patient the presence of tracheomalacia caused by megaesophagus compression secondary to achalasia probably responsible for episodes of acute airway obstruction and cardiopulmonary arrest.

Case Studies and Literature Review of Pneumococcal Septic Arthritis in Adults.

We conducted a retrospective study on all cases of pneumococcal septic arthritis (SA) in patients >18 years of age reported to the Picardie Regional Pneumococcal Network in France during 2005-2016. Among 1,062 cases of invasive pneumococcal disease, we observed 16 (1.5%) SA cases. Although SA is uncommon in adult patients, the prevalence of pneumococcal SA in the Picardie region increased from 0.69% during 2005-2010 to 2.47% during 2011-2016 after introduction of the pneumococcal 13-valent conjugate vaccine. We highlight the emergence of SA cases caused by the 23B serotype, which is not covered in the vaccine.

Plasma Exchange in the Management of Catastrophic Antiphospholipid Syndrome.

Objective. Report of a case of catastrophic antiphospholipid syndrome (CAPS) with multiple organ involvement leading to a life-threatening condition despite early combination corticosteroid and heparin therapy. Initiation of plasma exchange led to rapid improvement of the patient's general condition. Design. CASE REPORT: Setting. University teaching hospital medical intensive care unit. Patient. Single case: 52-year-old man hospitalized for catastrophic antiphospholipid syndrome (CAPS) with cardiac, renal, and cutaneous involvement. Despite early methylprednisolone and heparin therapy, the patient's condition progressively deteriorated, resulting in acute renal failure, right adrenal hemorrhage, and pulmonary involvement, leading to acute respiratory distress on day 6, requiring high-flow nasal cannula oxygen therapy with FiO2 of 1.0. Interventions. Plasma exchange was started on day 6. Endpoints and Main Results. A marked improvement of the patient's general condition was observed after initiation of plasma exchange, with successful weaning of oxygen therapy and normalization of platelet count, troponin, and serum creatinine within four days. Conclusions. This case illustrates the efficacy of plasma exchange in CAPS and the difficulty for physicians to determine the optimal timing of plasma exchange.

Oxidized low density lipoprotein increases RANKL level in human vascular cells. Involvement of oxidative stress.

Receptor Activator of NFκB Ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) have been shown to play a role not only in bone remodeling but also in inflammation, arterial calcification and atherosclerotic plaque rupture. In human smooth muscle cells, Cu(2+)-oxidized LDL (CuLDL) 10-50 µg/ml increased reactive oxygen species (ROS) and RANKL level in a dose-dependent manner, whereas OPG level was not affected. The lipid extract of CuLDL reproduced the effects of the whole particle. Vivit, an inhibitor of the transcription factor NFAT, reduced the CuLDL-induced increase in RANKL, whereas PKA and NFκB inhibitors were ineffective. LDL oxidized by myeloperoxidase (MPO-LDL), or other pro-oxidant conditions such as ultraviolet A (UVA) irradiation, incubation with H2O2 or with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, also induced an oxidative stress and enhanced RANKL level. The increase in RANKL in pro-oxidant conditions was also observed in fibroblasts and endothelial cells. Since RANKL is involved in myocardial inflammation, vascular calcification and plaque rupture, this study highlights a new mechanism whereby OxLDL might, by generation of an oxidative stress, exert a deleterious effect on different cell types of the arterial wall.

Oxidized low density lipoprotein enhanced RANKL expression in human osteoblast-like cells. Involvement of ERK, NFkappaB and NFAT.

BACKGROUND: Receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand/osteoprotegerin ratio is of crucial importance in osteoclast differentiation and thus in bone dysregulation diseases. METHODS: Receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand and osteoprotegerin were determined under oxidized low density lipoprotein treatment of human osteoblast-like cells. The involvement of oxidative stress, of the extracellular signal regulated kinase and of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells and nuclear factor of activated T cells was demonstrated. RESULTS: Cu(2+)-oxidized low density lipoprotein increased cell-associated and extracellular receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand levels whereas osteoprotegerin levels were not affected. The increase in receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand was parallel to the generation of reactive oxygen species provoked by Cu(2+)-oxidized low density lipoprotein. The lipid extract of Cu(2+)-oxidized low density lipoprotein, together with other forms of oxidized low density lipoproteins such as smooth muscle cell-oxidized low density lipoprotein and myeloperoxidase-oxidized low density lipoprotein, also induced an increase in reactive oxygen species and cell-associated receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand. The effect of Cu(2+)-oxidized low density lipoprotein was prevented by the antioxidant vitamin E, and mimicked by the prooxidant compounds hydrogen peroxide and buthionine sulfoximine. Inhibitors of mitogen activated protein kinase/extracellular signal regulated kinase (PD 98059), nuclear factor kappa-light-chain-enhancer of activated B cells (Ro 106-9920) and nuclear factor of activated T cells (Vivit) reduced the effect of Cu(2+)-oxidized low density lipoprotein on receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand expression. Cu(2+)-oxidized low density lipoprotein signaling was also reduced by vitamin E. GENERAL SIGNIFICANCE: This work describes a new molecular mechanism and elucidates the signaling pathway whereby oxidized low density lipoprotein, by means of its lipid moiety, can modulate the crosstalk between osteoblasts/osteoclasts and bone remodeling, leading to an eventual risk of osteoporosis.

Multiple myeloma cells directly stimulate bone resorption in vitro by down-regulating mature osteoclast apoptosis.

Multiple myeloma (MM) is characterized by devastating bone destruction mainly due to stimulation of osteoclastogenesis. However, whether MM cells can directly influence osteoclast apoptosis, a mechanism that would contribute to increase the number of active osteoclasts, has not been addressed yet. Herein, using authentic mature rabbit osteoclasts, we demonstrated that conditioned media (CM) prepared from U266 and RPMI8226 cells but not from LP-1 and OPM-2 cells, stimulated bone resorption and inhibited osteoclast apoptosis in a dose-dependent manner. The MM cells which exerted an anti-apoptotic effect secreted high amounts of M-CSF and addition of a neutralizing antibody against M-CSF reversed the CM effects. Imatinib mesylate, a tyrosine kinase inhibitor that can target the M-CSF receptor, also prevented the effect of CM. These findings suggest that M-CSF originating from MM cells may play a critical role in MM bone disease by decreasing osteoclast apoptosis.

Gastric MALT lymphoma presenting as Waldenström's macroglobulinemia without bone marrow involvement.

We report a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma with macroglobulinemia in a 59-year-old man who presented with melena. A computed tomography scan of the abdomen showed irregular thickening of the wall of the stomach, and endoscopic examination disclosed enlarged and inflammatory folds of the fundus. Histopathologic examination of gastric samples showed mucosal infiltration by small lymphocytes, which were positive for CD20 and negative for CD10 and CD23, confirming the diagnosis of gastric MALT lymphoma. Serum electrophoresis detected a monoclonal peak and immunoelectrophoresis revealed an immunoglobulin M kappa component. Bone marrow aspirate and biopsy results were normal. The patient received chemotherapy. After treatment, he was in complete remission, and the serum monoclonal component had disappeared. Our observation is uncommon because of important macroglobulinemia occurring in gastric MALT lymphoma without bone marrow involvement.

Thrombocytopenia in sarcoidosis.

BACKGROUND: Haematological manifestations in sarcoidosis are uncommon. The prevalence of thrombocytopenia in sarcoidosis is not well assessed. AIM: To describe the main characteristics and outcome of sarcoidosis associated with thrombocytopenia. METHODS: We described 2 personal cases and a complete record of all reports of thrombocytopenia in sarcoidosis was persuaded through a medline multi language computer search from 1972 until now. CASES REPORTS: In the first observation the clinical course was similar to immune thrombocytopenic purpura. Steroids were efficient. In the second, we have reported the first used of Rituximab in thrombocytopenia in sarcoidosis with a partial success. REVIEW OF THE LITERATURE: We identified three main physiopathological mechanisms among the 31 cases collected. Hypersplenism or splenomegaly was found in ten cases, granulomas in bone marrow were found in only four. Auto-immune thrombocytopenic purpura was suspected in the other cases. 23 patients had been treated with steroids, which proved effective in 21 cases (in association with intravenous immunoglobulin(IV-ig) or anti-D. Among the five cases for which steroids were non efficient, subsequent splenectomy allowed normalization of platelets count. Splenectomy was performed in seven cases, as a first intention treatment for five patients, and successful in four. One patient died of massive haemorrhage during the surgery. Among the 5 patients treated with IV-Ig, 4 had a complete response. CONCLUSION: Different physiopathological mechanisms are responsible of thrombocytopenia in sarcoidosis. Granulomas in bone marrow or hypersplenism may be involved. Immune thrombocytopenic purpura must be suspected in all other cases. Steroids remain the most effective treatment, and must be proposed in first intention.

Paecilomyces variotii fungemia in a patient with multiple myeloma: case report and literature review.

Infectious complications are common in patient with multiple myeloma. However, Paecilomyces variotii, a common saprophytic fungus, rarely causes human infection. We report the first case of P. variotii fungemia in this illness with good response with adapted anti-mycotic treatment.