Favorable Course Of Disease Research Articles

Functional T Cells Targeting NY-ESO-1 or Melan-A Are Predictive for Survival of Patients With Distant Melanoma Metastasis

To analyze the prognostic relevance of circulating T cells responding to NY-ESO-1, Melan-A, MAGE-3, and survivin in patients with melanoma with distant metastasis. We examined 84 patients with follow-up after analysis (cohort A), 18 long-term survivors with an extraordinarily favorable course of disease before analysis (> 24 months survival after first occurrence of distant metastases; cohort B), and 14 healthy controls. Circulating antigen-reactive T cells were characterized by intracellular cytokine staining after in vitro stimulation. In cohort A patients, the presence of T cells responding to peptides from NY-ESO-1, Melan-A, or MAGE-3 and the M category according to the American Joint Committee on Cancer classification were significantly associated with survival. T cells responding to NY-ESO-1 and Melan-A (hazard ratios, 0.29 and 0.18, respectively) remained independent prognostic factors in Cox regression analysis and were superior to the M category in predicting outcome. Median survival of patients possessing T cells responding to NY-ESO-1, Melan-A, or both was 21 months, compared with 6 months for all others. NY-ESO-1-responsive T cells were detected in 70% of cohort A patients surviving > 18 months and in 50% of cohort B patients. Melan-A responses were found in 42% and 47% of patients in cohorts A and B, respectively. In contrast, the proportion was only 22% for NY-ESO-1 and 23% for Melan-A in those who died within 6 months. The presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy.

1371 IL-22 PRODUCING T CELLS ARE ASSOCIATED WITH A FAVOURABLE DISEASE COURSE IN ALCOHOLIC HEPATITIS

1371 IL-22 PRODUCING T CELLS ARE ASSOCIATED WITH A FAVOURABLE DISEASE COURSE IN ALCOHOLIC HEPATITIS

HLA associations and Löfgren’s syndrome

Patients with sarcoidosis can be subgrouped according to organ engagement and clinical manifestations. One such subgroup is Löfgren’s syndrome (LS), constituting a distinct group of sarcoidosis patients with typical clinical manifestations, separate genetic associations and an immune response that seems to differ from that of non-LS patients. In particular, LS patients have strong associations with HLA-DRB1 alleles, and the well-known association with HLA-DRB1*03 is particularly striking. This particular HLA-DRB1 allele is also a very strong marker within that particular group of patients for a prognostically favorable disease course. This article will mainly discuss genetic associations with LS, and the possible implications of such associations.

Impact of MGMT promoter methylation in glioblastoma of the elderly.

2001 Background: Methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter identifies a subpopulation of glioblastoma patients with a more favorable course of disease and predicts a...

Changes in Peripheral CD4+CD25high Regulatory T Cells in the Acute-on-Chronic Liver Failure Patients with Plasma Exchange Treatment

The prevalence of CD4+CD25(high) regulatory T cells (Tregs) in patients with acute-on-chronic liver failure (AoCLF) who received plasma exchange (PE) and/or medical treatment was investigated. One hundred five patients with AoCLF in two groups (PE plus routine-care, n = 48 and routine-care, n = 57) were enrolled in our study. In the PE group, there were 27 survivors (27/48) while, in the routine-care group, there were 18 survivors (18/57), both after 30days treatment. Twenty-three healthy donors were used as the control group. Tregs were determined by flow cytometry serially. In the survivors, Tregs frequency were lower compared with the normal controls on admission and showed an up and down tendency; moreover, this frequency turned to the level as that in healthy subjects and was faster in the PE compared with the medical group while, among the nonsurvivors, Tregs stayed at a high level throughout the examination period. Importantly, an increased quantity of Tregs was associated with high mortality and reduced survival time of AoCLF patients. These data suggest that Tregs play a role in determining the patient's fate toward either a favorable or unfavorable clinical course of disease, and PE may represent a reliable hepatic support device for AoCLF.

Human induced CD4+CD25+FOXP3+ regulatory T cells are suppressive in vitro, but fail to suppress inflammation in vivo

BackgroundRegulatory T cells (Treg) are important to maintain immune homeostasis. Presence of Treg correlates with a favourable disease course in juvenile idiopathic arthritis (JIA) patients. A distinction within the Treg...

Mannose-binding lectin does not explain the course and outcome of pregnancy in rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) improves during pregnancy and flares after delivery. It has been hypothesized that high levels of the complement factor mannose-binding lectin (MBL) are associated with a favourable disease course of RA by facilitating the clearance of pathogenic immunoglobulin G (IgG) lacking galactose sugar moieties. During pregnancy, increased galactosylation of IgG and simultaneously increased MBL levels can be observed, with the latter being strictly related to maternal MBL genotypes. Therefore, increased MBL levels in concert with increased IgG galactosylation may be associated with pregnancy-induced improvement of RA. The objective of this study was to investigate whether MBL genotypes are associated with changes in RA disease activity and with changes in IgG galactosylation during pregnancy and in the postpartum period. We also studied the association between MBL genotypes and pregnancy outcomes in RA.MethodsSerum from 216 patients with RA and 31 healthy controls participating in the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) Study was collected before, during and after pregnancy. IgG galactosylation was determined by performing matrix-assisted laser desorption/ionization time of flight mass spectrometry. Disease activity was determined using the internationally recognized Disease Activity Score 28 (DAS28). MBL genotypes were determined. The pregnancy outcome measures studied were gestational age, birth weight, miscarriage and hypertensive disorders.ResultsNo association was found between the MBL genotype groups and changes in RA disease activity (P = 0.89) or changes in IgG galactosylation (patients, P = 0.75, and controls, P = 0.54) during pregnancy and in the postpartum period. Furthermore, MBL genotype groups were not related to the studied pregnancy outcome measures.ConclusionsThis study does not provide evidence for a role for MBL in the improvement of RA during pregnancy or for a role for MBL in pregnancy outcome.

Treatment and Prognosis of Gastric MALT Lymphoma

Mucosa-associated lymphoid tissue (MALT) lymphomas represent 7% of all non-Hodgkin’s lymphomas and can arise from any extranodal site; however, at least one-third of them present as a primary gastric lymphoma. Eradication of Helicobacter pylori (H. pylori) with antibiotics should be employed as the sole initial treatment of H. pylori-positive gastric MALT lymphoma. H. pylori eradication can induce lymphoma regression and long-term clinical disease control in most patients. In H. pylori-negative cases or patients who fail antibiotics therapy, irradiation and systemic therapies should be applied depending on the stage of disease; surgery has not been shown to achieve superior results in comparison with more conservative approaches in various trials. Lymphoma with diffuse large cell infiltration should be treated according to the recommendations for diffuse large cell lymphoma. H. pylori eradication resulted in complete lymphoma remission in the majority of cases. Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of H. pylori had a favorable disease course without oncological treatment. A watch and wait strategy with regular endoscopies and biopsies appears to be safe and may become the approach of choice in this situation. Nevertheless, long-term careful endoscopic and systemic (blood counts and minimal adequate radiological or ultrasound examinations) follow-up once per year is recommended for all patients. This article is a review for the current treatment and prognosis of gastric MALT lymphoma. (Korean J Helicobacter Up Gastrointest Res 2011;11:165-169)

Favourable course of disease after incomplete remission on 131I therapy in children with pulmonary metastases of papillary thyroid carcinoma: 10 years follow-up

The aim of this study is to report on a collective of 20 children from Belarus who had developed papillary thyroid carcinoma with pulmonary metastases after the Chernobyl disaster. In all children fractionated radioiodine therapy (RIT) was ceased before achieving complete remission due to a lack of further effects of (131)I therapy and an increased risk of pulmonary fibrosis. The 20 children (12 girls) were treated with (131)I using 50MBq/kg body weight for thyroid remnant ablation and 100MBq/kg for further therapy in intervals of 5-12months. After five to six courses and a cumulative activity of about 24GBq (131)I no further RIT was conducted; the median thyroglobulin (TG) was 56μg/l at this time. All patients were followed for at least 10years after cessation of RIT using diagnostic whole-body scintigraphy, CT of the chest, lung function testing and stimulated TG measurements every 1-3years. During follow-up after the last RIT a continuous decline of values for TG levels of ∼35% per year was observed between individual visits. The median Tg level at the time of cessation of (131)I therapy was 56 µg/l; however, at the last visit 16 of 20 patients had a TG level ≤10μg/l (median 2.4μg/l). Neither on diagnostic radioiodine whole-body scan nor on CT was progression of lung metastases observed. No significant pulmonary fibrosis developed. In spite of incomplete remission of thyroid cancer at cessation of RIT, a continuing spontaneous decline of TG and clinically stable partial remissions were observed in this collective of children. Therefore, if RIT does not show further effects, the administration of further courses should be handled restrictively.

Effects of social support on the clinical course of Crohnʼs disease

Social support has been found to be protective from adverse health effects of psychological stress. We hypothesized that higher social support would predict a more favorable course of Crohn's disease (CD) directly (main effect hypothesis) and via moderating other prognostic factors (buffer hypothesis). Within a multicenter cohort study we observed 597 adults with CD for 18 months. We assessed social support using the ENRICHD Social Support Inventory. Flares, nonresponse to therapy, complications, and extraintestinal manifestations were recorded as a combined endpoint indicating disease deterioration. We controlled for several demographic, psychosocial, and clinical variables of potential prognostic importance. We used multivariate binary logistic regression to estimate the overall effect of social support on the odds of disease deterioration and to explore main and moderator effects of social support by probing interactions with other predictors. The odds of disease deterioration decreased by 1.5 times (95% confidence interval [CI]: 1.2-1.9) for an increase of one standard deviation (SD) of social support. In case of low body mass index (BMI) (i.e., 1 SD below the mean or <19 kg/m(2) ), the odds decreased by 1.8 times for an increase of 1 SD of social support. In case of low social support, the odds increased by 2.1 times for a decrease of 1 SD of BMI. Low BMI was not predictive under high social support. The findings suggest that elevated social support may favorably affect the clinical course of CD, particularly in patients with low BMI.

Can mannose-binding lectin explain the course and outcome of pregnancy in rheumatoid arthritis?

Rheumatoid arthritis (RA) improves during pregnancy and flares after delivery. It has been hypothesised that high levels of the complement factor mannose binding lectin (MBL) are associated with a favourable...

Top-down therapy for IBD: rationale and requisite evidence

Several trials have shown that early treatment of Crohn's disease with immunomodulators and anti-TNF agents leads to a superior clinical outcome, including healing of the mucosa, compared with standard therapy alone. Mounting evidence indicates that mucosal healing is associated with a reduced risk of complications, and a reduced need for surgeries and hospitalizations. In the SONIC trial, a combination of the standard azathioprine immunomodulator therapy and infliximab, an anti-TNF agent, had more potent anti-inflammatory effects than either drug alone in patients with Crohn's disease who had evidence of active inflammation. These findings and those from rheumatoid arthritis trials have prompted the investigation of early initiation of immunomodulator (standard or anti-TNF) therapy for Crohn's disease, in suitable patients, which has led to substantial improvements in disease management. Careful selection of patients is, however, essential given the potential risk of toxic effects from these therapies and the fact that some patients with IBD will have a favorable disease course without them. Identification of suitable patients, however, remains a challenge, as genetic, phenotypic and environmental factors have not yet been identified that can be used for routine assessment and selection is mainly based on clinical criteria.

Besonderheiten entzündlich-rheumatischer Erkrankungen im höheren Lebensalter

Polymyalgia rheumatica and arteritis temporalis are characteristic rheumatic diseases of advanced age. Concomitantly, peripheral arteritis of large vessels occurs at higher ages. Required diagnostics and current recommendations for the therapy of these diseases are discussed in the present review. Rheumatoid arthritis can develop at advanced age (late onset rheumatoid arthritis/LORA) or patients, whose rheumatoid arthritis commenced at younger age, have grown old with their chronic disease (young onset rheumatoid arthritis/YORA). Considerable differences between LORA and YORA can be found for clinical patterns (worse functional capacity in LORA), for laboratory parameters (lower rheumatoid factor and ACPA in LORA), and for outcome. Rheumatoid factor negative LORA predominantly shows a favourable disease course than one with a positive rheumatoid factor. Radiological progression is more prominent in LORA patients with rheumatoid factor than in the corresponding YORA patients. Furthermore, at the same disease duration LORA patients suffer from more comorbid conditions than YORA patients. LORA patients are treated less aggressively, in particular, biologics are less frequently prescribed. Late onset systemic lupus erythematosus (LO-SLE) shows in general a milder disease activity than SLE of early onset, but is accompanied by more cardiovascular, ocular and musculo-skeletal damage. Therefore LO-SLE is not a benign disease. The specific features of rheumatic diseases at advanced age deserve closer attention in an increasingly older-growing population.

Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be managed safely by a watch and wait strategy: experience from a large international series

Background:Eradication of Helicobacter pylori is the established initial treatment of stage I MALT (mucosa associated lymphoid tissue) lymphoma. Patients with minimal persisting lymphoma infiltrates after successful eradication of H pylori...

Reconstructive plastic surgery in the treatment of vulvar carcinomas

Objective The results obtained using plastic surgery reconstruction in 207 patients with a primary or recurrent vulvar carcinoma were analyzed with regard to the surgical procedures applied, pre-treatment and post-operative findings, along with the long-term oncological disease course. Study design Standardized data concerning the surgical procedures applied and clinical factors were collected in a databank and statistically analyzed. Results The flaps employed were termed either ‘local’ (cutaneous or fasciocutaneous; n = 84) or ‘regional’ (myocutaneous, n = 123). For local flaps, the rate of secondary healing was 31%, dropping to 20% for regional flaps. Such healing disturbances often affected the donor region and did not lead to lasting clinical problems such as stenosis or distortion. Severe disturbances of wound healing (loss of more than 10%) were not observed in local flaps, whereas such problems were encountered in 5.9% of regional flaps. Gluteal thigh flaps were most frequently applied and were also the most successful type of myocutaneous reconstruction. Therapy was selected on an individual basis according to tumor status. Conclusion Plastic surgery reconstruction broadens the range of operative therapies available for the treatment of vulvar carcinomas, especially those at an advanced stage or recurrent tumors, and leads to a favorable oncological disease course as well as improved cosmetic results.

Kinetics of Immune Responses and Tumor Burden in Patients with Indolent B Cell Lymphomas Receiving Recombinant Idiotype Vaccination as the Sole Treatment.

Immunization of patients with B-cell non-Hodgkin's lymphoma with the individual idiotype expressed by the malignant clone can induce tumor-specific immune responses that correlate with improved remission duration and survival rates after cytoreductive chemotherapy. We have developed a production method for a recombinant idiotype vaccine based on expression of Fab fragments in E. coli. Intradermal administration of this vaccine mixed with lipid-based adjuvant and subcutaneous coadministration of GM-CSF has excellent immunogenicity as demonstrated by a high and idiotype-specific immune response rate in a phase I trial in advanced lymphoma patients with a severely impaired immune status (Bertinetti et al., Cancer Research 2006). Of a cohort of 15 patients with newly diagnosed or relapsed indolent B cell malignancies who had not been treated with conventional cytoreductive therapy and received 6 monthly immunizations of this idiotype vaccine, we observed 6 cases (40%) with objective quantitative evidence of tumor regression. 5 of these patients were in primary “watch and wait” situation for indolent NHL, and 1 follicular lymphoma patient had recurrence of nodal disease after a complete remission achieved in the phase I trial. At weeks 0, 8, 24, 36, and 52 after initiation of vaccination, staging examinations were performed including enumeration of circulating tumor cells by quantitative real-time PCR, and immune responses were assessed by ELISPOT and ELISA. Beginning with the 4th vaccination, evidence for reduction of nodal disase was noted in 5 cases, 4 of which achieved an objective partial response after all 6 scheduled immunizations according to standard staging criteria. These patients received continuing vaccinations in intervals of 1–3 months, and no progression has occurred after a follow-up of 9–32 months. Of 6 patients who had detectable lymphoma cells in the peripheral blood, 4 showed a continuous, at least 10fold decrease of the number of circulating lymphoma cells during the course of the vaccination. Two of the partial responders had never evidence for circulating tumor cells. A T cell response to the vaccine developed in 4/5 evaluated patients with evidence of tumor regression and in 3/6 patients without evidence for a clinical response. These cellular responses were maintained at stable levels during the vaccination and continued to be present 6 months after the last vaccination. Humoral immune responses were induced in 5/5 patients with declining tumor burden and in 2/6 non-responders. In 3 cases, the anti-idiotypic antibody titers declined after 6 months. In cases where anti-idiotype antibodies of IgM and IgG isotype occurred, IgM preceded the appearance of IgG. All objective clinical responders mounted a combined cellular and humoral immune response. The temporal association of immune responses with tumor regression provides support for the assumption that recombinant idiotype vaccination in the chosen format may play a causal role for a favorable disease course in previously untreated indolent lymphomas and may hence obviate the need for cytoreductive chemotherapy for extended time periods.

Mediators of apoptosis Fas and FasL predict disability progression in multiple sclerosis over a period of 10 years

TNF-α, IL-12p35, IL-12p40, IL-4, IL-10, TGF-β1, CCR3, CXCR3, CCR5, Fas and FasL mRNA levels in PBMC of 25 multiple sclerosis (MS) patients were quantified at baseline by real-time PCR according to a post-hoc study design. The baseline values of the different markers were analysed with respect to their correlation with the increase in disability over a period of 10 years. High levels of Fas mRNA were associated with a favourable disease course in relapsing-remitting (RR) MS (R2 = 0.74, P = 0.0001, n = 13), as measured by the Expanded Disability Status Scale (EDSS); high levels of FasL mRNA were associated with relatively mild disease progression (R2 = 0.86, P = 0.0001, n = 12) in secondary progressive (SP) MS. These findings suggest that Fas-mediated apoptosis plays a major role in the mechanism underlying long-term disease progression in MS.

Inversions of chromosomes 2 and 6 in mantle cell lymphoma. Cytogenetic, FISH, and molecular studies

Inversions are infrequent events in hematological malignancies. We here report the cytogenetic, fluorescence in situ hybridization (FISH), and molecular studies of 2 patients diagnosed with mantle cell lymphoma (MCL) that showed inversions of chromosomes 2 and 6 as part of complex karyotypes. Both patients showed a cytogenetically identical inv(6)(p23q11) detected as a secondary aberration. In addition, both patients had a derivative chromosome 2 which originated by partial deletion of the short arm and a pericentric inversion with different breakpoints on the long arm: der(2)del(2)(p21)inv(2)(p21q11) and der(2)del(2)(p21)inv(2)(p21q13), respectively. The presence of t(11;14)(q13;q32) was confirmed by interphase FISH and by molecular study. Residual normal cells were found in both cases. The patients showed a different clinical evolution with a poor outcome for one case and a favorable course of the disease for the other one. The review of the literature in MCL showed a total of 9 inversions affecting different chromosomes. Considering that inversions are very infrequent events in MCL, our findings could be important for detecting genes potentially involved in development and/or progression of this aggressive non-Hodgkin lymphoma subtype.

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors of the gastrointestinal tract. Activating KIT or PDGFRA (platelet-derived growth factor receptor α) mutations have been shown to be a major force in GIST pathogenesis. Recently, a previously undescribed N659K PDGFRA exon 14 mutation has been reported in GISTs. The purpose of this study was to evaluate the frequency of GISTs with PDGFRA exon 14 mutations and define the clinicopathologic profile of such tumors. In all, 200 GISTs negative for mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were evaluated for PDGFRA exon 14 mutations by PCR amplification and direct sequencing. Mutations were found in 11 of 119 (9%) gastric GISTs. None of the 81 GISTs from other than gastric location had such a PDGFRA mutation. A majority of these mutations (eight cases) represented simple 2125C>A or C>G missense mutations, leading to substitution of the lysine for asparagine (N659K). However, in two cases, 2123A>T missense mutations leading to substitution of the tyrosine for asparagine (N659Y) was found instead. Of 11 PDGFRA N659-mutant GISTs, 10 had pure epithelioid morphology. One tumor had mixed, predominantly spindle and focally epithelioid cell morphology. Frequency of PDGFRA N659-mutant GISTs among pure epithelioid GISTs was almost 19%. Immunohistochemically, the majority (64%) of these tumors lacked KIT expression or showed only focal scattered KIT positivity. Tumor size ranged from 2.5 to 16 cm (average 7.1 cm). Low mitotic activity, ≤5 mitoses/50 high power field was detected in six GISTs including larger, >5 cm tumors. Based on mitotic activity and tumor size, six tumors were classified as probably benign with very low malignant potential. Low to moderate malignant potential and high malignant potential was suggested in three and two tumors, respectively. In four cases with moderate or high malignant potential GISTs, a long-term follow-up (average 235.5 months) showed favorable course of disease.

Molecular and Clinical Analysis of a Midwest Cohort of B-CLL Patients Utilizing the Immunoglobulin VH 1-69 Gene.

The prognostic power of immunoglobulin (Ig) somatic mutation status in B cell chronic lymphocytic leukemia (B-CLL) is widely appreciated and has served as the rationale to systematically determine this molecular feature in B-CLL patients. Consistent with other reports, our study of Ig mutation status in a large cohort of B-CLL patients (n=599) found the most commonly used Ig heavy chain variable (VH) region gene was VH 1–69. The VH1–69 gene is of particular interest as there are numerous reports demonstrating that VH1–69 expressing B-CLL cells predominantly express the 51p1-like allele in an unmutated (UM) form and it is frequently associated with use of the D gene segment, D3-3; the J gene segment, JH6; and a relatively long third, complementarity-determining region (CDR3). Despite molecular definition of a commonly used form of VH1–69 in B-CLL, the clinical significance of CLL B cell usage of this prototypic form of VH1–69 remains to be determined. The goal of this study, therefore, was to perform a molecular and clinical analysis on our cohort of B-CLL patients expressing the VH1–69 gene. Our cohort consisted of 19 females and 55 males, with 89.5% expressing UM Ig VH. The 51p1-like allele was present in 75.7% of patients and the predominant D region used was D3 (64.7%). Patients in our cohort were classified by Rai risk as follows: 20 low (28.2%), 40 intermediate (56.3%), and 11 high (15.5%). For those patients with Rai stage available, analysis of specific D and J regions resulted in 16 D3-3/JH6 (26.7%); 14 D3-3/non-JH6 (23.3%); 16 non-D3-3/JH6 (26.7%); and 14 non-D3-3/non-JH6 (23.3%). Despite observing an overwhelming majority of leukemic cells with UM Ig VH, and the known relationship between mutation status and disease progression, it is interesting that our cohort included almost 30% with a low Rai risk. Of note, Ig VH mutation status did not segregate with Rai risk group or VH1–69 allele use (although few patients overall were mutated). However, an UM Ig VH status was associated with a CDR3 length >20 (p = 0.001) and with use of the JH6 segment (p = 0.003). When mutation status was analyzed in concert with specific use of the D3-3 allele, no relationship emerged; however, when this D region allele was analyzed for JH6 vs non-JH6 usage, combination of the D3-3 allele with JH6 was significantly associated with an UM Ig VH status (p = 0.004). Moreover, when J and D segment usage was analyzed in concert with Rai stage group, a significant (p = 0.019) relationship emerged between paired use of D3-3 and a JH6 segment and advanced (intermediate/high) Rai stage. Strikingly, only 1 of 18 VH1–69 patients with low Rai risk for whom D and J data were available expressed the specific combination of D3-3 and JH6. Although analysis of a larger cohort is clearly required to more formally and fully evaluate these relationships, to our knowledge, this is the first suggestion that D and J usage in VH1-69 expressing B-CLL patients correlates with advanced stages of disease. Because Ig VH usage is not believed to change over the course of disease, it is tempting to speculate that VH1–69 B-CLL patients that do not express the prototypic VH1–69 receptor may have a more favorable disease course. In summary, these data add further support to the notion that there is selection for specific Ig receptors in B-CLL and that the antigenic specificity of certain receptors may be associated with risk of progression.