Navigating Through Surgical Implications of Helicobacter pylori: An Up-to-Date Comprehensive Literature Review.

Helicobacter pylori, a gram-negative bacterium, has been identified as a major contributor to gastrointestinal diseases, ranging from gastritis and peptic ulcers to more severe complications such as gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. While pharmacological eradication therapies have been successful in managing H. pylori-associated diseases, the implications of this bacterium on surgical interventions remain a topic of ongoing research and clinical consideration. This comprehensive review aims to elucidate the intricate surgical implications of H. pylori infection. Recent data on the well-known relationship between and the development of gastroduodenal diseases, including peptic ulcers and gastric cancer, is analyzed. Concurrently, Helicobacter pylori infection may have a role in promoting colonic carcinogenesis and, more interestingly, it has also been linked to biliary tract cancers. The review highlights the evolving landscape of H. pylori management in the context of surgical interventions, accentuating the need for further research to delineate optimal strategies for preoperative screening, eradication therapies, and their impact on surgical outcomes and long-term patient prognosis. Comprehending the surgical ramifications of H. pylori infection remains crucial, emphasizing the significance of interdisciplinary approaches and ongoing research effort aimed at enhancing patient care.

Clinico-biological features and outcome of patients with splenic marginal zone lymphoma with histological transformation.

We describe 36 patients with splenic marginal zone lymphoma (SMZL) with transformation (SMZL-T), including 15 from a series of 84 patients with SMZL diagnosed at the Hospital Clinic of Barcelona (HCB) and 21 diagnosed with SMZL-T in other centres. In the HCB cohort, the cumulative incidence of transformation at 5 years was 15%. Predictors for transformation were cytopenias, hypoalbuminaemia, complex karyotype (CK) and both the Intergruppo Italiano Linfomi (ILL) and simplified Haemoglobin, Platelet count, lactate dehydrogenase (LDH) and extrahilar Lymphadenopathy (HPLL)/ABC scores (P < 0·05). The only independent predictor for transformation in multivariate analysis was CK [hazard ratio (HR) 4·025, P = 0·05]. Patients with SMZL-T had a significantly higher risk of death than the remainder (HR 3·89, P < 0·001). Of the 36 patients with SMZL-T, one developed Hodgkin lymphoma and 35 a diffuse large B-cell lymphoma, 71% with a non-germinal centre phenotype. The main features were B symptoms, lymphadenopathy, and high serum LDH. CK was observed in 12/22 (55%) SMZL-T and fluorescence in situ hybridisation detected abnormalities of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and/or BCL6 in six of 14 (43%). In all, 21 patients received immunochemotherapy, six chemotherapy, one radiotherapy and three splenectomy. The complete response (CR) rate was 61% and the median survival from transformation was 4·92 years. Predictors for a worse survival in multivariate analysis were high-risk International Prognostic Index (HR 5·294, P = 0·016) and lack of CR (HR 2·67, P < 0·001).

Bacterial infection-driven lymphomagenesis.

PURPOSE OF REVIEW: The first convincing evidence for a causal relationship between bacterial infection and lymphomagenesis came from the link between gastric lymphoma and chronic Helicobacter pylori gastritis. This review will summarize the current epidemiological, clinical, and biological evidence of a causative role of bacteria in the development of malignant lymphomas, particularly, the extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type. RECENT FINDINGS: Other microorganisms have been associated with specific extranodal lymphoma sites with variable and not always definitive, evidence, including Chlamydia psittaci , Borrelia burgdorferi , Campylobacter jejuni and, most recently, Coxiella Burnetii . According to most plausible models, lymphoma growth is a consequence of continuous antigenic stimulation induced by chronic infection. However, some evidence of a direct oncogenic role of H. pylori has been provided, too. SUMMARY: Lymphomas are not the result of a single cause but multifactorial diseases, influenced by a variety of genetic and environmental elements. Hence, ascertaining the specific contribution of bacterial infections is not always easy. Nevertheless, the eradication of the associated chronic infection may result in sustained lymphoma regression. Moreover, the association between infections and lymphoma may offer opportunities for reducing lymphoma incidence by preventing the predisposing infections or treating them early.

Chemotherapy is an efficient treatment in primary CNS MALT lymphoma.

BACKGROUND: Mucosae-associated lymphoid tissue (MALT) lymphomas are a rare and poorly understood form of primary central nervous system lymphoma (PCNSL). The aim of this study was to better describe these tumors, their management and their long-term prognosis. METHODS: Patients with primary CNS MALT lymphoma (PCNSML) were retrospectively selected from the database on PCNSL of the Pitié-Salpêtrière Hospital. RESULTS: Of 662 PCNSL, 11 (1.7%) PCNSML (9 females and 2 males, median age: 56 years) were selected. The median time from first symptoms to diagnosis was 13 months. Location was dural in 8 cases and parenchymal in 3 cases. The disease was multifocal/diffuse in 7 cases. In first line, all patients received chemotherapy (high-dose methotrexate (HD-MTX) based chemotherapy (n = 4) and non-HD-MTX-based chemotherapy (n = 7)), preceded by surgery in 4 cases. None received radiotherapy. According to the IPCG (International PCNSL Collaborative Group) criteria, the overall response rate was 7/11 (64%). At latest news, 5 patients had persistent contrast enhancement, stable with no treatment since a median of 57 months, raising the question of complete response despite persisting contrast enhancement. No patient developed neurotoxicity except for one patient who subsequently received radiotherapy. The median follow-up was 109 months. The median progression-free survival was 78.0 months and the 10-year overall survival rate was 90%. CONCLUSION: This is the largest series demonstrating that chemotherapy is an efficient treatment in PCNSML, with an excellent long-term outcome and the absence of neurotoxicity, and calling into question the relevance of the IPCG criteria for the evaluation of response.

Lymphoepithelial lesions in the salivary glands of primary Sjögren's syndrome patients: the perfect storm?

In patients with primary Sjögren's syndrome (pSS), inflamed salivary gland (SG) tissue may contain lymphoepithelial lesions (LELs). LELs are histopathological phenomena whereby B cells are present in hyperplastic ductal epithelium of the SG. Despite the potential role of LELs in pSS pathogenesis, studies on their formation, detection, and prevalence in benign lesions (not complicated with lymphoma) are scarce. Recent evidence however shows that LELs are present in approximately half of the patients with pSS, both in minor and major SGs. Migration of a small number of B cells into the epithelium appears to be a critical initial step in LEL formation. These intra-epithelial B cells are proliferative, exhibit an innate-like phenotype, and may be linked to MALT lymphoma development. Alongside intra-epithelial B cells, the hyperplastic epithelial partner in LELs also engages in the local immune reaction. Epithelial cells are a source of cytokines and chemokines, with CXCL10 in particular playing a potential role in LEL formation. Importantly, LELs also have a negative impact on the maintenance of SG homeostasis by SG progenitor cell (SGPC) populations, likely due to dysregulation of SGPC lineage commitment or induction of plasticity. In conclusion, LEL formation mirrors a perfect storm of B and epithelial cell interaction culminating in increased risk of B cell derailment and SGPC dysregulation in pSS patients. We therefore argue that attenuation of LEL formation is an important treatment goal to preserve SG function and prevent B cell derailment in pSS.

Hepatitis C virus-associated indolent B-cell lymphomas: A review on the role of the new direct antiviral agents therapy.

Several studies have suggested that hepatitis C virus (HCV) may be the causative agent of some B-cell non-Hodgkin lymphomas (B-NHL). Several authors have demonstrated that pegylated interferon (Peg-IFN) plus ribavirin (RBV) can revert indolent low-grade B-NHL by inducing HCV eradication. Presently, the combination therapy (IFN plus RBV) has been abandoned since the direct antiviral agents (DAAs) have shown very high efficacy in achieving sustained virologic response (SVR) (range: 95%-100%). This review analyzed DAAs efficacy in HCV-associated indolent low-grade NHL, providing a detailed literature review. Overall, 122 B-cell NHL patients were treated with DAAs: complete/partial hematological response, particularly in those with marginal zone lymphoma, was obtained in most cases. Hematological response, obtained either with DAAs or IFN-based therapy, was similar. Nonetheless, DAAs therapy showed better tolerability and higher SVR. A fraction of the patients, despite SVR, underwent hematologic relapse or progression. In these cases, a recovery treatment with immunotherapy, or chemoimmunotherapy, had to be planned. In conclusion, data obtained from published studies mostly agree that HCV eradication with DAAs should be considered as the first-line treatment in HCV-related NHL. In fact, the chronic viral stimulation of the immune system might be the primary pathogenic mechanism in disease development and progression.

Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma.

OBJECTIVES: To explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren's syndrome (SS) patients. METHODS: Salivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production. RESULTS: Transcriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4+CXC-motif chemokine receptor 5 (CXCR5)+programmed cell death protein 1 (PD1)+ICOS+ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4+CD45RO+ICOS+PD1+ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5+CD4+PD1+ICOS+Foxp3- Tfh-cells and a uniquely expanded population of CXCR5-CD4+PD1hiICOS+Foxp3- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α). CONCLUSIONS: Overall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.

Helicobacter pylori: A Review of Current Diagnostic and Management Strategies.

As one of the most prevalent infections globally, Helicobacter pylori (H. pylori) continues to present diagnostic and therapeutic challenges for clinicians worldwide. Diagnostically, the "test-and-treat" strategy is the recommended approach for healthcare practitioners when managing this potentially curable disease. The choice of testing method should be based on several factors including patient age, presenting symptoms, and medication use, as well as test reliability, availability, and cost. With rising antibiotic resistance, particularly of macrolides, care must be taken to ensure that therapy is selected based on regional resistance patterns and prior antibiotic exposure. In the USA, macrolide antibiotic resistance rates in some areas have reached or exceeded a generally accepted threshold, such that clarithromycin triple therapy may no longer be an appropriate first-line empiric treatment. Instead, bismuth quadruple therapy should be considered, while levofloxacin-based or alternative macrolide-containing therapies are also options. Once treated, it is essential to test for eradication as untreated H. pylori is associated with serious complications including peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. This review article aims to consolidate current knowledge of H. pylori infection with a particular emphasis on diagnostic and treatment strategies.

[Clinicopathological analysis of mucosa associated lymphoid tissue lymphoma secondary to Sjögren' s syndrome in salivary gland].

OBJECTIVE: To analyze the clinicopathological characteristics of mucosa associated lymphoid tissue (MALT) lymphoma secondary to Sjögren' s syndrome (SS) (SS-MALT lymphoma) in salivary gland and to explore the value of the combined application of histopathological morphology, protein expression and molecular phenotype in pathological diagnosis and prognostic evaluation of SS-MALT lymphoma. METHODS: Sixteen patients with SS-MALT lymphoma were collected from 260 patients who were diagnosed with SS in Peking University School and Hospital of Stomatology from January 1997 to December 2016. Twelve patients with non-MALT lymphoma secondary to SS (non-SS-MALT lymphoma) in salivary gland were selected as controls. The clinical data of the patients were retrospectively reviewed and analyzed. All the patients were followed up until December 20, 2019. Hematoxylin-eosin staining, immunohistochemistry, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) techniques were used to observe the histologic characteristics and to detect the manifestations of light chain restrictive expression, immunoglobulin (Ig) gene clonal rearrangement, chromosome translocation and gene abnormality, so as to evaluate their values in pathological diagnosis and prognostic evaluation. RESULTS: The malignant transformation rate of SS to MALT lymphoma was about 6.15%, ranged from 3 to 240 months, during which 2 patients died due to high-level deterioration. Microscopically, the acini of the glandular tissue were atrophied and destroyed. The tumor cells dominated by central cell-like lymphocytes grew diffusely, destroying the epithelial islands. All SS-MALT lymphoma cases were positive in CD20 and Pax5. Half of them had the Ki-67 proliferation index of 10% or less, and half greater than 10%. 93.75% cases expressed AE1/AE3 protein, which showed the residual glandular epithelium. All the tumor cells were negative in CD3ε, and the plasma cells were detected by CD138 antigen. The light chain restrictive expression of κ and λ was 37.5% in SS-MALT lymphoma group. The positive detection rates of immunoglobulin heavy chain (IgH)-FR1, IgH-FR2, IgH-FR3, immunoglobulin kappa chain (IgK)-A, and IgK-B in SS-MALT lymphoma group were 33.3%, 53.3%, 33.3%, 20.0%, and 26.7%, respectively, and 93.3% when together used with IgH and IgK. The positive rates of the MALT1, IGH and BCL6 genes with dual color break-apart probes were 36.4%, 27.3% and 27.3%, and the detection rate of chromosome translocation and gene abnormality by applying the three probes was 72.7%. CONCLUSION: There are no specific histological characteristics and protein phenotypes in the histologic diagnosis of SS-MALT lymphoma in salivary gland. The combined application of histopathological manifestations, immunohistochemistry, PCR and FISH techniques helps the accurate pathologic diagnosis of the disease. Although SS-MALT lymphoma is considered as an indolent lymphoma with a relatively favorable prognosis, the regular return visit and long-term follow-up should be conducted to detect the clues of recurrence and advanced deterioration.

Helicobacter pylori (HP) infection alone, but not HP-induced atrophic gastritis, increases the risk of gastric lymphoma: a case-control study in Japan.

Infection with Helicobacter pylori (H. pylori) is associated with an increased risk of gastric malignant lymphoma. The chronic inflammation of gastric mucosa by H. pylori infection induces lymphomagenesis. Although this chronic mucosal inflammation also results in atrophic gastritis, evidence supporting the possible significance of atrophic gastritis in gastric lymphomagenesis is scarce. Here, to evaluate the association between gastric mucosal atrophy and the risk of gastric lymphoma, we conducted a matched case-control study at Aichi Cancer Center focusing on the attribution of H. pylori infection status and pepsinogen (PG) serum levels. In total, 86 patients with gastric lymphoma (including 49 cases of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and 24 cases of diffuse large B cell lymphoma (DLBCL)) and 1720 non-cancer controls were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results failed to show a statistically significant association between atrophic gastritis and the risk of gastric lymphoma. The adjusted ORs of positive atrophic gastritis relative to negative for overall gastric lymphoma, MALT lymphoma, DLBCL, and other lymphomas were 0.77 (95% CI 0.45-1.33), 0.65 (0.30-1.39), 1.03 (0.38-2.79), and 0.84 (0.22-3.29), respectively. In contrast, a positive association between overall gastric lymphoma and H. pylori infection was observed (OR = 2.14, 95% CI 1.30-3.54). A consistent association was observed for MALT lymphoma, DLBCL, and other lymphomas with ORs of 1.96 (1.00-3.86), 1.92 (0.74-4.95), and 5.80 (1.12-30.12), respectively. These findings suggest that H. pylori infection triggers gastric lymphoma but that epithelial changes due to atrophic gastritis do not inherently affect the development of gastric lymphoma.

Prognostic markers of lymphoma development in primary Sjögren syndrome.

Sjögren syndrome is a systemic autoimmune disease that principally affects women between the fourth and sixth decades of life who present with sicca symptomatology caused by dryness of the main mucosal surfaces. The clinical spectrum of Sjögren syndrome extends from dryness to systemic involvement. Since 1978, Sjögren syndrome has been closely associated with an enhanced risk of lymphoma, one of the most severe complications a patient may develop. Primary Sjögren syndrome patients have a 10-44-fold greater risk of lymphoma than healthy individuals, higher than that reported for systemic lupus erythematosus and rheumatoid arthritis. The close link between lymphoma and Sjögren syndrome is clearly exemplified by the very specific type of lymphoma arising in Sjögren syndrome patients, mainly low-grade B-cell lymphomas (predominantly a marginal zone histological type) with primary extranodal involvement of the major salivary glands (overwhelmingly parotid), with a primordial role of cryoglobulinemic-related markers (both clinical and immunological). The most recent studies support a higher number of risk factors detected in an individual leads to a higher lymphoma risk. A close follow-up of high-risk groups with longitudinal assessments of all known risk factors, including cryoglobulin-related markers and EULAR Sjögren's syndrome disease activity index measurement in particular, is mandatory.

Marginal Zone Lymphoma: State-of-the-Art Treatment.

OPINION STATEMENT: Despite being the second most common indolent non-Hodgkin's lymphoma (iNHL), marginal zone lymphoma (MZL) remains largely understudied, and given its underlying disease heterogeneity, it is challenging to define a single treatment approach for these patients. For localized disease, local therapy is recommended such as triple therapy for H. pylori in gastric extranodal MZL, splenectomy for splenic MZL, and radiotherapy for nodal MZL. For disseminated disease with low tumor burden, a watch and wait or single-agent rituximab can be used. However, for symptomatic disease, a similar approach to follicular lymphoma (FL) can be used with chemoimmunotherapy approaches such as bendamustine and rituximab. High FDG uptake is not common in MZL and is not diagnostic by itself of transformation to high-grade lymphoma but informs the choice of the site to be biopsied. Transformation into a large B cell lymphoma is treated with R-CHOP-like regimens. Patients with relapsing disease after at least one CD20-based therapy have several recently approved chemotherapy-free options including B cell receptor inhibitors such ibrutinib (approved specifically in MZL) and immunomodulatory agents such as lenalidomide and rituximab (FDA approved in MZL and FL). Phosphoinositide 3-kinase (PI3K) inhibitors have shown excellent activity in iNHL, specifically in MZL, with breakthrough designation status for copanlisib and umbralisib, allowing off label use of this class of agents in clinical practice. With the availability of prospective clinical trials using chemo-free approaches, specifically those targeting abnormal signaling pathways activated in MZL tumors and its microenvironment, treating physicians are encouraged to enroll patients on these clinical trials in order to better understand the underlying biology, mechanisms of response, and resistance to current therapies and help design future rationale combination strategies.

Malignant Helicobacter pylori-Associated Diseases: Gastric Cancer and MALT Lymphoma.

Helicobacter pylori is the first bacterium formally recognized to play a causative role in human malignancies, gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Evidence accumulates that H. pylori cagA-positive strains play a crucial role in the neoplastic transformation of mammalian cells. The cagA-encoded CagA protein is delivered into the host cells via bacterial type IV secretion, where it interacts with and thereby aberrantly activates pro-oncogenic phosphatase SHP2. The CagA-SHP2 interaction requires tyrosine phosphorylation of CagA at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif. The incidences of gastric cancer in East Asian countries such as Japan, China, and Korea are among the highest worldwide. A vast majority of H. pylori circulating in East Asia produce a CagA variant termed East Asian CagA, which possesses the SHP2-binding EPIYA motif (EPIYA-D) that is substantially diverged in sequence from the SHP2-binding EPIYA motif (EPIYA-C) of CagA isolated in the rest of the world (Western CagA). Tyrosine-phosphorylated EPIYA-D interacts with SHP2 approximately two orders of magnitude stronger than tyrosine-phosphorylated EPIYA-C does. The strong SHP2 binding of East Asian CagA is achieved by a cryptic interaction between the phenylalanine residue located at the +5 position from the phospho-tyrosine in EPIYA-D and a small hollow on the N-SH2 phosphopeptide-binding floor, the latter of which cannot be created by the corresponding aspartic acid in EPIYA-C. Thus, a variation in a single amino-acid residue determines the magnitude for the pathogenic/oncogenic action of CagA, which may influence the worldwide landscape in the incidence of H. pylori-associated malignancies, especially gastric cancer.

The Role of Host Genetic Polymorphisms in Helicobacter pylori Mediated Disease Outcome.

The clinical outcome of infection with the chronic gastric pathogen Helicobacter pylori is not the same for all individuals and also differs in different ethnic groups. Infection occurs in early life (<3 years of age), and while all infected persons mount an immune response and develop gastritis, the majority of individuals are asymptomatic. However, up to 10-15% develop duodenal ulceration, up to 1% develop gastric cancer (GC) and up to 0.1% can develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The initial immune response fails to clear infection and H. pylori can persist for decades. H. pylori has been classified as a group one carcinogen by the WHO. Interestingly, development of duodenal ulceration protects against GC. Factors that determine the outcome of infection include the genotype of the infecting strains and the environment. Host genetic polymorphisms have also been identified as factors that play a role in mediating the clinical outcome of infection. Several studies present compelling evidence that polymorphisms in genes involved in the immune response such as pro and anti-inflammatory cytokines and pathogen recognition receptors (PRRs) play a role in modulating disease outcome. However, as the number of studies grows emerging confounding factors are small sample size and lack of appropriate controls, lack of consideration of environmental and bacterial factors and ethnicity of the population. This chapter is a review of current evidence that host genetic polymorphisms play a role in mediating persistent H. pylori infection and the consequences of the subsequent inflammatory response.

Ocular adnexal marginal zone lymphoma arising in a patient with IgG4-related ophthalmic disease.

A 41-year-old man was diagnosed with immunoglobulin G4-related disease (IgG4-RD) in both eyelids 4 years ago and exhibited good response to steroid therapy. However, rapid swelling of the right eyelid lesion was recently observed. As IgG4-RD progression was suspected, biopsy was performed. Although the histology was consistent with IgG4-RD, the infiltrating large atypical lymphoid cells showed immunoglobulin light-chain restriction and IgH gene rearrangement. Consequently, he was diagnosed with extranodal marginal zone lymphoma with abundant IgG4-positive cells.

The evaluation of disease activity in Sjögren's syndrome based on the degree of MALT involvement: glandular swelling and cryoglobulinaemia compared to ESSDAI in a cohort study.

OBJECTIVES: To investigate if indicators of a heavier involvement of mucosa-associated lymphoid tissue (MALT) in primary Sjögren's syndrome (pSS), i.e. persistent salivary gland (SG) swelling and cryoglobulinaemia, might better evaluate the lymphoma risk compared to the ESSDAI. Therefore, the current concept of disease activity of pSS should be re-evaluated, based solely on ESSDAI. METHODS: A cohort of 255 pSS patients, including 30 pSS with B-cell lymphoma, was investigated. Three subgroups were distinguished, i.e. pSS developing lymphoma in the follow-up (n=12), pSS with lymphoma at cohort inclusion (n=18), and control pSS not developing lymphoma in the follow-up (n=225). SG swelling, cryoglobulinaemia and ESSDAI were evaluated at baseline, in the follow-up to one year before lymphoma diagnosis, and at lymphoma diagnosis. RESULTS: SG swelling and/or cryoglobulinaemia at baseline were significantly higher (p=0.0003) in pSS patients evolving into lymphoma if compared to pSS controls, while ESSDAI showed no significant difference. Both SG swelling and cryoglobulinaemia persisted and sometimes developed ex novo in the follow-up. SG swelling and cryoglobulinaemia were present in 24/30 (80%) cases the time of lymphoma diagnosis, and lymphoma itself was usually of MALT/marginal zone histotype (90%), leading to peculiar manifestation of lymphoma in pSS. CONCLUSIONS: The autoimmune and lymphoproliferative involvement of MALT is the biological substrate of pSS. If this involvement is heavier, as reflected by SG swelling and cryoglobulinaemia, disease activity may be considered higher, and the risk of lymphoma is increased. The current concept and evaluation of activity of pSS, based solely on the ESSDAI, needs revision.

Long-term effects of the new direct antiviral agents (DAAs) therapy for HCV-related mixed cryoglobulinaemia without renal involvement: a multicentre open-label study.

OBJECTIVES: To investigate the long-term effects and safety of new direct anti-viral agents (DAAs) in patients with hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC) without renal involvement. METHODS: The study enrolled 22 consecutive patients, 19 received sofosbuvir-based regimen and three patients received other DAAs, individually tailored according to latest guidelines. As of December 2016, the median length of follow-up was 17 months (range 13-21). RESULTS: Extra-hepatic manifestations at enrollment were: purpura and arthralgia (12 cases), peripheral neuropathy (10 cases) and marginal zone B- lymphomas (2 cases). After a four-week DAA therapy, all patients became HCV- negative. Moreover, after 48 weeks since the beginning of DAA treatment, sustained regression of purpura and arthralgias was observed respectively in eight and in nine cases; peripheral neuropathy improved in seven cases, and cryocrit median values decreased from three (1-20) at baseline to two (1-12) after 48 weeks. Two cases with indolent marginal zone lymphomas did not show any haematological response: size and number of the involved nodes remained unchanged. In addition, the monoclonal B-cell population found in the peripheral blood in four cases did not disappear after recovery from HCV- RNA. Mild side effects occurred in nine patients, but six patients developed ribavirin-related anaemia requiring reduction of ribavirin dose. CONCLUSIONS: DAA therapy is safe and effective to eradicate HCV in MC, but seems associated with satisfactory clinical response in mild or moderate cryoglobulinaemic vasculitis and no response in B-NHL.

Salivary S100A8/A9 in Sjögren's syndrome accompanied by lymphoma.

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune inflammatory disease that affects the exocrine glands. The absence of early diagnostic markers contributes to delays in its diagnosis. Identification of changes in the protein profile of saliva is considered one of the promising strategies for the discovery of new biomarkers for SS. OBJECTIVE: To identify salivary protein biomarkers with potential for use in discriminating between different lymphoma risk subgroups of SS. METHOD: Parotid and whole mouth saliva samples were collected from patients with SS, including those in subgroups at higher risk of developing or with confirmed lymphoma, non-SS sicca disease controls and healthy subjects. An initial proteomics analysis by mass spectrometry (LCMSMS) identified S100A8/A9 as a biomarker and was followed by validation with an enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant differences were found in levels of S100A8/A9 in parotid saliva but not whole mouth saliva between patients with SS compared with healthy and disease control subjects (P = 0.001 and 0.031, respectively). Subgroups of patients with SS based on lymphoma risk showed significant differences in salivary levels of S100A8/A9. CONCLUSION: The results suggest that salivary levels of S100A8/A9 can aid in differentiating between SS, disease control and healthy control subjects, especially the subgroups of SS with lymphoma or at higher risk of lymphoma.

Orbital Extranodal Marginal Zone Lymphoma Following Radiotherapy: A Report of 2 Cases.

PURPOSE: To present 2 patients in whom orbital radiation preceded the development of periorbital extranodal marginal zone lymphoma by more than a decade and to investigate the likelihood of this representing irradiation-induced malignancy. METHODS: Retrospective chart review and histopathologic study with immunohistochemistry of 2 cases. RESULTS: The first patient was a 58-year-old woman who developed an orbital mass within the vicinity of the lateral rectus muscle 17 years after external beam proton radiation therapy for an inferotemporal choroidal melanoma. The second patient was a 32-year-old woman who developed a mass in the right lacrimal gland 12 years after external beam photon radiation therapy for chronic inflammatory dacryoadenitis. Histopathologic and immunohistochemical studies confirmed orbital extranodal marginal zone lymphoma in both cases. Retrospective review of older histopathologic slides from the second patient revealed underlying immunoglobulin G4-related disease. DISCUSSION: The unusual sequence of events in these 2 cases raises the question of whether orbital radiation may in rare instances promote the development of orbital extranodal marginal zone lymphoma. The literature pertaining to irradiation-induced secondary malignancy in the orbit is reviewed. CONCLUSIONS: Clinicians should consider the possibility of a secondary malignancy when evaluating a patient with an orbital mass and a history of prior local radiation exposure.

The P2X7 receptor-NLRP3 inflammasome complex predicts the development of non-Hodgkin's lymphoma in Sjogren's syndrome: a prospective, observational, single-centre study.

BACKGROUND: P2X7 receptor (P2X7R), trigger of acute inflammatory responses via the NLRP3 inflammasome, is hyperfunctioning in patients with Sjögren's syndrome (SS), where it stimulates IL-18 production. Some patients with SS develop a mucosa-associated lymphoid tissue non-Hodgkin's lymphoma (MALT-NHL). OBJECTIVES: To prospectively evaluate the involvement and the putative prognostic role of this inflammatory pathway in the development of MALT-NHL. METHODS: A total of 147 women with SS have been prospectively followed for a mean of 52 months, relating the expression and function of the P2X7R-inflammasome axis in salivary glands and circulating lymphomonocytes to the prognosis and the degree of the disease. RESULTS: At baseline, gene expression of P2X7R and of the inflammasome components NLRP3, caspase-1 and IL-18 increased according to the presence of germinative centres and was higher in autoantibody-positive individuals and strongly higher in those developing a MALT-NHL over the follow-up. Glandular expression of IL-18 was threefold higher in MALT-NHL than in controls or in the other patients with SS. P2X7R did not colocalize with generic markers of inflammatory infiltrate, like CD20, being selectively expressed by epithelial cells. P2X4R, sharing functional characteristics with P2X7R, did not differ in SS and controls. The increased P2X7R gene and protein expression was tissue specific, no difference being observed in peripheral lymphomonocytes between SS with MALT-NHL and SS not developing MALT-NHL. CONCLUSION: We propose the P2X7R-inflammasome axis as a novel potential pathway involved in both SS exocrinopathy and lymphomagenesis, reinforcing the hypothesis of a key role of IL-18, via its increased P2X7R-mediated production, in the pathogenesis of lymphoproliferative malignancies, and opening novel opportunities for the early diagnosis of lymphoproliferative complications and the development of potential targeted therapies.