The impact of pre-operative depression on pain outcomes after major surgery: a systematic review and meta-analysis.

Symptoms of depression are common among patients before surgery. Depression may be associated with worse postoperative pain and other pain-related outcomes. This review aimed to characterise the impact of pre-operative depression on postoperative pain outcomes. We conducted a systematic review of observational studies that reported an association between pre-operative depression and pain outcomes after major surgery. Multilevel random effects meta-analyses were conducted to pool standardised mean differences and 95%CI for postoperative pain scores in patients with depression compared with those without depression, at different time intervals. A meta-analysis was performed for studies reporting change in pain scores from the pre-operative period to any time-point after surgery. Sixty studies (n = 501,962) were included in the overall review, of which 18 were eligible for meta-analysis. Pre-operative depression was associated with greater pain scores at < 72 h (standardised mean difference 0.97 (95%CI 0.37-1.56), p = 0.009, I2 = 41%; moderate certainty) and > 6 months (standardised mean difference 0.45 (95%CI 0.23-0.68), p < 0.001, I2 = 78%; low certainty) after surgery, but not at 3-6 months after surgery (standardised mean difference 0.54 (95%CI -0.06-1.15), p = 0.07, I2 = 83%; very low certainty). The change in pain scores from pre-operative baseline to 1-2 years after surgery was similar between patients with and without pre-operative depression (standardised mean difference 0.13 (95%CI -0.06-0.32), p = 0.15, I2 = 54%; very low certainty). Overall, pre-existing depression before surgery was associated with worse pain severity postoperatively. Our findings highlight the importance of incorporating psychological care into current postoperative pain management approaches in patients with depression.

Postoperative outcomes in surgical patients with obstructive sleep apnoea diagnosed by sleep studies: a meta-analysis and trial sequential analysis.

Identifying surgical patients with obstructive sleep apnoea may assist with anaesthetic management to minimise postoperative complications. Using trial sequential analysis, we evaluated the impact of obstructive sleep apnoea diagnosed by polysomnography or home sleep apnoea testing on postoperative outcomes in surgical patients. Multiple databases were systematically searched. Outcomes included: total postoperative complications, systemic complications (cardiovascular, respiratory, neurological, renal, infectious) and specific complications (atrial fibrillation, myocardial infarction, combined hospital and intensive care unit re-admission, mortality). The pooled odds ratios of postoperative complications were evaluated by the Mantel-Haenszel method random-effects model. Meta-analysis and meta-regression were conducted, and the GRADE approach was used to evaluate the certainty of evidence. Twenty prospective cohort studies with 3756 patients (2127 obstructive sleep apnoea and 1629 non-obstructive sleep apnoea) were included (9 in non-cardiac surgery and 11 in cardiac surgery). Postoperative complications were almost two-fold higher with obstructive sleep apnoea, OR (95%CI) 1.92 (1.52-2.42), p < 0.001; certainty of evidence, moderate. Obstructive sleep apnoea was associated with a 1.5 times increased risk of postoperative cardiovascular complications, OR (95%CI) 1.56 (1.20-2.02), p = 0.001; certainty of evidence, moderate; an almost two-fold increase in respiratory complications, OR (95%CI) 1.91 (1.39-2.62), p < 0.001; certainty of evidence, moderate; and hospital and ICU re-admission, OR (95%CI) 2.25 (1.21-4.19), p = 0.01; certainty of evidence, low. Trial sequential analysis showed adequate information size for postoperative complications. Baseline confounding factors were adjusted by meta-regression, and the sub-group analysis did not materially change our results. This increased risk occurred especially in patients in whom obstructive sleep apnoea had been newly diagnosed, emphasising the importance of pre-operative screening.

Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia.

Analysis of the immunoglobulin receptor (IGR) variable heavy- and light-chain sequences on 17 hepatitis C virus (HCV)-associated non-Hodgkin lymphomas (NHLs) (9 patients also had type II mixed cryoglobulinemia [MC] syndrome and 8 had NHL unrelated to MC) and analysis of intraclonal diversity on 8 of them suggest that such malignant lymphoproliferations derive from an antigen-driven pathologic process, with a selective pressure for the maintenance of a functional IgR and a negative pressure for additional amino acid mutations in the framework regions (FRs). For almost all NHLs, both heavy- and light-chain complementarity-determining regions (CDR3) showed the highest similarity to antibodies with rheumatoid factor (RF) activity that have been found in the MC syndrome, thus suggesting that a common antigenic stimulus is involved in MC syndrome and in HCV-associated lymphomagenesis. Moreover, because HCV is the recognized pathologic agent of MC and the CDR3 amino acid sequences of some HCV-associated NHLs also present a high homology for antibody specific for the E2 protein of HCV, it may be reasonable to speculate that HCV E2 protein is one of the chronic antigenic stimuli involved in the lymphomagenetic process. Finally, the use of specific segments, in particular the D segment, in assembling the IgH chain of IgR seems to confer B-cell disorders with the property to produce antibody with RF activity, which may contribute to the manifestation of an overt MC syndrome.

Pre-malignant and malignant lymphoproliferations in an HCV-infected type II mixed cryoglobulinemic patient are sequential phases of an antigen-driven pathological process.

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis characterized by the presence in the serum of a monoclonal cryoprecipitable IgM with rheumatoid factor (RF) activity. Hepatitis C virus (HCV) has been recognized as its major etiologic factor. Because MC frequently evolves into overt B-cell non-Hodgkin's lymphoma (NHL), chronic HCV infection is hypothesized to lead to both benign and malignant lymphoproliferative disease. In this study, we investigated mutations in the V(H) and V(K) genes of the B-cell clone originating the overt B-cell lymphoma in a subject with MC. Mutational patterns were analyzed longitudinally in two bone marrow biopsies obtained at the stage of MC, as well as in multiple involved tissues (bone marrow, liver, and peripheral blood cells) at the stage of overt NHL. Hybridization of variable-diversity-joining (VDJ) PCR products with a probe specific for the neoplastic clone indicated that the lymphoma originated from one of the clones over-stimulated during MC. This clone producing an IgM highly homologous to a protein with RF specificity may explain the MC syndrome in the patient. Moreover, the presence of an IgH ongoing mutation process and the expression of an Ig antigen receptor significantly homologous to an anti-HCV protein support the hypothesis that the MC syndrome and the subsequent evolution to NHL are antigen-driven lymphoproliferative processes possibly sustained by HCV. Furthermore, the marked reduction in intra-clonal diversity in the last bone marrow biopsy obtained at the stage of overt NHL points out a minor dependence of the cells on the antigen-driven mechanism, although an intrinsic propensity of the neoplastic cell to undergo replacement mutations cannot be excluded.

Oligoclonal non-neoplastic B cell expansion is the key feature of type II mixed cryoglobulinemia: clinical and molecular findings do not support a bone marrow pathologic diagnosis of indolent B cell lymphoma.

OBJECTIVE: Type II mixed cryoglobulinemia (type II MC) is often characterized by features of indolent B cell lymphoma (IBCL) found on pathologic examination of bone marrow, whereas the clinical evidence does not indicate a neoplastic disorder. To better address the issue of indolent malignant versus nonmalignant bone marrow lymphoproliferation underlying type II MC, molecular analyses of B cell clonality were performed in the present study, in conjunction with clinical and pathologic characterization. METHODS: Polymerase chain reaction DNA amplification of immunoglobulin heavy chain genes was performed in bone marrow biopsy specimens obtained from 15 selected patients with type II MC, all infected with hepatitis C virus. Five of them had also developed overt B cell lymphoma (OBCL) during followup. Bone marrow features were consistent with IBCL in 9 of the 15 patients (group 1) and with reactive lymphoplasmacytosis in 6 of the 15 (group 2). RESULTS: An oligoclonal B cell expansion was detected in 6 of 9 baseline bone marrow lesions from group 1 patients (biclonal or monoclonal expansion in the remaining 3 cases), and in 6 of 6 from group 2 patients. OBCL was always monoclonal. Selected lesions were analyzed by clonospecific hybridization and by cloning and sequence analysis in patients who had developed OBCL at followup. In 4 of 5 cases, OBCL did not originate from the dominant B cell clones that were overexpanded in the putative neoplastic baseline bone marrow lesions. OBCL clones showed significant homology with rheumatoid factor database sequences. CONCLUSION: Based on the present results, as well as on evidence from previous studies of liver lesions, oligoclonal non-neoplastic B cell proliferation in the course of chronic infection-related inflammation appears to be the key feature of type II MC. Of note, molecular evidence from target tissues supports the clinical findings both at the time of type II MC diagnosis and in cases of OBCL complication. Bone marrow pathologic findings resembling those of IBCL should thus be considered in the light of clinical and molecular evidence.

Gastric mucosa as an additional extrahepatic localization of hepatitis C virus: viral detection in gastric low-grade lymphoma associated with autoimmune disease and in chronic gastritis.

The hepatitis C virus (HCV) has been linked to B-cell lymphoproliferation and autoimmunity, and has been localized in several tissues. The clinical observation of an HCV-infected patient with Sjögren's syndrome (SS) and Helicobacter pylori (HP) positive gastric low-grade B-cell non-Hodgkin's lymphoma (NHL), which did not regress after HP eradication, led us to investigate the possible localization of HVC in the gastric microenvironment. HCV genome and antigens were searched in gastric biopsy specimens from the previously mentioned case, as well as from 9 additional HCV-infected patients (8 with chronic gastritis and 1 with gastric low-grade B-cell NHL). HCV-specific polymerase chain reaction (PCR) and immunohistochemistry procedures were used. The gastric B-cell NHL from the patient with SS was characterized by molecular analyses of B-cell clonality. HCV RNA was detected in both the gastric low-grade B-cell NHL and in 3 out of 6 gastric samples from the remaining cases. HCV antigens were detected in the residual glandular cells within the gastric B-cell NHL lesions, in glandular cells from 2 of the 3 additional gastric lesions that were HCV positive by PCR, and in 1 additional chronic gastritis sample in which HCV-RNA studies could not be performed. By molecular analyses, of immunoglobulin genes, the B-cell NHL from the patient with SS was confirmed to be a primary gastric lymphoma, subjected to ongoing antigenic stimulation and showing a significant similarity with rheumatoid factor (RF) and anti-HCV- antibody sequences. Our results show that HCV can localize in the gastric mucosa.

T cell receptor repertoire in B cell lymphoproliferative lesions in primary Sjögren's syndrome.

OBJECTIVE: Studies have analyzed T cell receptor (TCR)-Vbeta in benign, minor salivary or lacrimal gland, or kidney lesions in Sjögren's syndrome (SS). We investigated SS related lymphoproliferative lesions. METHODS: By "family" reverse transcriptase polymerase chain reaction, we studied the expression of 20 different TCR-Vbeta families in parotid lymphoproliferative lesions and peripheral blood lymphocytes (PBL) from 7 patients with primary SS, in PBL from 6 primary SS patients with no associated lymphoproliferative disorder, and in activated PBL from 2 healthy controls. T cell clonal expansion was investigated in 10 Vbeta families (i.e., the most expanded ones and those previously implicated in SS pathogenesis) by single strand conformation polymorphism (SSCP) analysis. Frozen sections from parotid gland specimens were tested by immunohistochemistry for the expansion of selected Vbeta families. Viral infection within the parotid lesions and serum autoantibody response were also studied. RESULTS: An unrestricted Vbeta pattern was observed. The most widely expressed Vbeta family in parotid lesions was Vbeta2, and Vbeta immunohistochemistry results were concordant with Vbeta mRNA findings. A similar pattern was observed in PBL, although the Vbeta2 family was expressed at lower levels. The parotid/PBL ratio was occasionally > 1.8-2.0 (indicative of local Vbeta overexpression) in different Vbeta families. T cell expansion proved to be largely polyclonal by SSCP analysis, and scattered T cell clonotypes were detected within different Vbeta families, with a different pattern from patient to patient. CONCLUSION: Our observations in SS related lymphoproliferative lesions largely reflect previous evidence in fully benign lesions. The pathogenetic events involved in autoimmune benign lesions in SS may then persist and play a role in SS related lymphoproliferative disorders. The link between the observed TCR-Vbeta repertoire and specific local triggering (auto)antigens remains to be elucidated.

Rarity of microsatellite genomic instability in B-cell non-Hodgkin's lymphomas in hepatitis C virus-infected patients.

Several groups have emphasized the likely implication of the hepatitis C virus (HCV) in a fraction of B-cell non-Hodgkin's lymphomas. Since only a minority of patients with HCV infection and monoclonal mixed cryoglobulinaemia develop overt lymphoma, the identification of predisposing factors has relevant clinical implications. The replication error phenotype (RER+), as revealed by widespread microsatellite instability, is caused by defects in DNA mismatch repair genes, and has been frequently disclosed in subsets of B-cell lymphomas with underlying infection and chronic inflammation. We therefore investigated the occurrence of the RER+ phenotype in a series of eight consecutive B-cell NHLs in patients with chronic infection by HCV. A polymerase chain reaction-based assay was used to analyse an extended panel of 15 microsatellite loci. Microsatellite instability was not observed in six tumour samples in any locus; the two remaining cases showed instability at only one locus. Therefore genetic instability by defects in DNA mismatch repair genes should not represent the general mechanism predisposing to overt lymphoma in HCV-infected patients. Although a clearer definition of HCV-related B-cell disorders should better address future studies on genetic instability in larger series, we recommend additional oncogenetic pathways as the target of further research.

Epstein-Barr virus strains with latent membrane protein-1 deletions: prevalence in the Italian population and high association with human immunodeficiency virus-related Hodgkin's disease.

Six Epstein-Barr virus (EBV)-related lymphoproliferative disorders were investigated to verify whether the EBV strain harbored by neoplastic cells had the same EBNA-2 and latent membrane protein-1 (LMP-1) DNA sequences of the virus carried by normal lymphocytes of the same patients. Within each case, the analysis of neoplastic lymph nodes, reactive lymphadenopathies, and/or EBV+ spontaneous lymphoblastoid cell lines gave concordant results with respect to type-specific EBNA-2 region and LMP-1 gene. In particular, five cases showed the same deletion in the 3' end of the LMP-1 gene in both normal and neoplastic cells. We also determined the prevalence of LMP-1 deletions in a large series of normal peripheral blood mononucleated cells (PBMCs) from Italian individuals. The analysis showed that 50% (9 of 18) of PBMCs from human immunodeficiency virus (HIV)-seronegative donors carried a 30-bp deletion in the C-terminal portion of the LMP-1 gene, whereas a nondeleted fragment was amplified in about 44% (8 of 18) of the cases. Only one sample (5.6%) showed the amplification of a full-length LMP-1 band together with a deleted fragment. Similarly, PBMCs from HIV-infected patients showed an almost equivalent prevalence of full-length (17 of 37, 46%) and deleted (16 of 37, 43.2%) LMP-1 fragments, whereas about 11% of samples (4 of 37) showed evidence of double infections. Of note, deletions in the LMP-1 gene were detected with similar prevalence values in EBV+ Hodgkin's disease (HD) (13 of 30, 43.3%) and non-Hodgkin's lymphoma (NHL) (2 of 5, 40%) cases from HIV-seronegative patients and in HIV-related, EBV+ NHLs (4 of 7, 57.1%). Conversely, a 30-bp LMP-1 deletion was found in 10 of 12 HIV-associated HD cases (83%), a prevalence significantly higher than that detected in HIV-unrelated HD (P = .01). These findings indicate that: (1) the same EBV strain carrying LMP-1 deletions is harbored by normal and neoplastic cells of patients with EBV+ disorders, ruling out that these mutations might result from immunoselection phenomena; (2) in the Italian population, the prevalence of LMP-1 deletion mutants is comparable to that of EBV strains with full-length LMP-1; (3) HIV-induced immunosuppression is not associated with an increased prevalence of LMP-1 deletions in PBMCs; and (4) HIV-related HD cases, but not those of HIV-seronegative Italian patients, are closely correlated with the presence of LMP-1 deletions, suggesting that infection with these strains may increase the risk of developing HD in the HIV setting.

Retinoids irreversibly inhibit in vitro growth of Epstein-Barr virus-immortalized B lymphocytes.

Natural and synthetic retinoids have proved to be effective in the treatment and prevention of various human cancers. In the present study, we investigated the effect of retinoids on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines (LCLs), since these cells closely resemble those that give rise to EBV-related lymphoproliferative disorders in the immunosuppressed host. All six compounds tested inhibited LCL proliferation with no significant direct cytotoxicity, but 9-cis-retinoic acid (RA), 13-cis-RA, and all-trans-RA (ATRA) were markedly more efficacious than Ro40-8757, Ro13-6298, and etretinate. The antiproliferative action of the three most effective compounds was confirmed in a large panel of LCLs, thus appearing as a generalized phenomenon in these cells. LCL growth was irreversibly inhibited even after 2 days of treatment at drug concentrations corresponding to therapeutically achievable plasma levels. Retinoid-treated cells showed a marked downregulation of CD71 and a decreased S-phase compartment with a parallel accumulation in Gzero/ G1 phases. These cell cycle perturbations were associated with the upregulation of p27 Kip1, a nuclear protein that controls entrance and progression through the cell cycle by inhibiting several cyclin/cyclin-dependent kinase complexes. Unlike what is observed in other systems, the antiproliferative effect exerted by retinoids on LCLs was not due to the acquisition of a terminally differentiated status. In fact, retinoid-induced modifications of cell morphology, phenotype (downregulation of CD19, HLA-DR, and s-Ig, and increased expression of CD38 and c-Ig), and IgM production were late events, highly heterogeneous, and often slightly relevant, being therefore only partially indicative of a drug-related differentiative process. Moreover, EBV-encoded EBV nuclear antigen-2 and latent membrane protein-1 proteins were inconstantly downregulated by retinoids, indicating that their growth-inhibitory effect is not mediated by a direct modulation of viral latent antigen expression. The strong antiproliferative activity exerted by retinoids in our experimental model indicates that these compounds may represent a useful tool in the medical management of EBV-related lymphoproliferative disorders of immunosuppressed patients.

B-cell clonality and infection with Helicobacter pylori: implications for development of gastric lymphoma.

BACKGROUND: Although Helicobacter pylori has been implicated in the pathogenesis of gastric mucosa associated lymphoid tissue (MALT) and MALT lymphoma, it is not known how it may trigger these lesions and whether there is an identifiable pre-neoplastic stage. AIMS: To investigate the relation between MALT, H pylori infection, and B-cell clonality (a potential marker of pre-neoplastic lesions). PATIENTS: 141 subjects with simple dyspepsia. METHODS: Gastric biopsy specimens from all patients were examined for MALT and H pylori. Of these, 25 consecutive MALT positive specimens were scored for features of MALT lymphoma and VDJ clonality studied by polymerase chain reaction. RESULTS: Overall, prevalence was 62% for H pylori and 46% for MALT. VDJ clonality was frequent in the sub-group studied (nine of 25), mostly associated with lymphoid follicles (eight of nine or 89%), and with a high scoring for MALT lymphoma. VDJ clonality was equally frequent in patients with and without H pylori (seven of 20 and two of five or 35% and 40% respectively). CONCLUSIONS: B-cell clonality is unexpectedly common in subjects with simple dyspepsia and MALT raising clinical management questions. These findings also suggest that the cascade MALT formation--B-cell clonality--MALT lymphoma may not be uniquely associated with H pylori infection.

The role of molecular analyses of B-cell and T-cell clonality in the study of B-cell lymphomagenesis.

While the simple detection of B-cell clonality does not imply B-cell malignancy, comprehensive analyses of B-cell clonality are crucial to investigate the pathobiology of B-cell lymphoproliferative disorders. Our recent studies in patients with Sjögren's syndrome have highlighted how multiple molecular analyses of B-cell clonality (Southern blot, polymerase chain reaction, single strand conformation polymorphism, and DNA sequence analysis) in prelymphomatous lesions may be of great value in helping to define the stages of progression towards low-grade malignancy. The study of T-cell expansion may also be important in investigations of the pathobiology of the different stages of B-cell lymphoproliferation (fully benign, pseudolymphomatous, or definitely malignant), which may still be T-cell-and antigen/ autoantigen-dependent.

The relevance of VDJ PCR protocols in detecting B-cell clonal expansion in lymphomas and other lymphoproliferative disorders.

AIMS AND BACKGROUND: The detection of immunoglobulin heavy chain variable (VH)-diversity (DH)-joining (JH) region gene rearrangement by polymerase chain reaction (VDJ PCR) has been recently proposed as a rapid approach to assess B-cell clonality in lymphoproliferative disorders. The aim of the present study was to determine the efficacy of VDJ PCR in a wide spectrum of lymphoproliferative disorders previously characterized by immunohistochemistry and Southern blot (SB). METHODS: 83 SB-rearranged B-cell non-Hodgkin's lymphomas (NHL) of different histotype, 22 cases of SB-unrearranged classical Hodgkin's disease (HD), 18 cases of HIV-related reactive lymphadenopathy, and 4 frankly pre-lymphomatous lesions (MESA) in the course of Sjögren's syndrome were investigated by 2 different VDJ PCR protocols (FR3, FR2). RESULTS: The detection rate in NHL was 64% and 71% using the protocols FR3 and FR2, respectively. However, the overall VDJ PCR efficacy increased to 81% by combining the results of both protocols. In addition, differences in the combined, as well as in the single FR3 or FR2 protocol efficacy, were noted in the different NHL subgroups. B-cell clonality was also detected in 4/22 (18%) SB-unrearranged classical HD cases and in 2/18 (11%) reactive lymphadenopathy cases, whereas it was demonstrated in all the MESA lesions, 2 of them being SB-negative. CONCLUSIONS: VDJ PCR represents a useful and rapid technique to detect B-cell clonality in NHL, although with some differences depending on the NHL histotype and the panel of primers employed. The technique may also be of value to investigate the possible progression of early B-cell clonal expansion into frankly B-cell malignancy and to contribute to the controversy about the clonal lineage origin of the putative HD malignant cells.

Local cytokine expression in the progression toward B cell malignancy in Sjögren's syndrome.

OBJECTIVE: Sjögren's syndrome (SS) has been indicated as an ideal human model to investigate B cell lymphomagenesis. Our aim was to investigate similarities or differences in cytokine expression in both prelymphomatous and frank B cell lymphomatous SS lesions, as well as in SS related lesions versus SS unrelated malignant B cell non-Hodgkin's lymphomas. METHODS: The mRNA expression of interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-6, IL-6R, IL-9, IL-10, IL-12, tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and transforming growth factor beta (TGF-beta) was analyzed by a sensitive reverse transcriptase polymerase chain reaction technique in 10 SS tissue samples from 10 consecutive patients [7 nonmalignant parotid myoepithelial sialadenitis (MESA) lesions with evidence of B cell clonal expansion, and 3 B cell non-Hodgkin's lymphomas] as well as a series of 11 SS unrelated B cell non-Hodgkin's lymphomas. RESULTS: IL-1, IL-2, IL-3, IL-6, IL-6R, IL-10, IL-12, IFN-gamma, TNF-alpha, and TGF-beta mRNA was expressed in all or in the vast majority of the samples analyzed. IL-4 mRNA was detected in 2/3 SS related and in 3/11 SS unrelated non-Hodgkin's lymphomas, while SS related MESA samples were characterized by an IL-4 negative pattern and lacked IL-3 or IFN-gamma expression in 3/7 cases and in 2/7 cases, respectively. CONCLUSION: Many cytokines may be involved in the evolution of prelymphomatous to definite B cell malignant lesions in SS, as well as in the development of SS unrelated B cell non-Hodgkin's lymphomas. A putative pathobiological role of the IL-12/IL-4 balance, in the presence of cytokines that may sustain B cell proliferation (i.e., IL-3, IL-6, IL-10), may represent a major point for future research. Finally, our data reinforce the view of SS as a human model of B cell lymphomagenesis.