Depressed NK cell activity of peripheral blood mononuclear cells in untreated Hodgkin's disease: Enhancing effect of interferon in vitro

Natural killer (NK) cell activity of unseparated peripheral blood mononuclear cells from 30 untreated patients with Hodgkin's disease and 22 age- and sex-matched normal controls was evaluated using the classical K 562 cells as targets. A significant defect was demonstrated in the patients with stage I-II and seemed to be more profound in patients with advanced disease (stage III-IV) and in those with B symptoms. The differences between subgroups of patients, however, were not statistically significant, mostly because of the wide dispersion of individual data. Pre-incubation of effector cells with alpha A leucocyte recombinant interferon led to a clear increase in NK cell activity in 4 of 6 patients tested, showing that depressed NK activity in Hodgkin's disease is still susceptible to the enhancing effect of interferon, at least in some patients.—     

Antibody response to pneumococcal vaccine in patients with early stage Hodgkin's disease

Antibody response to pneumococcal vaccination was studied in 76 patients with Hodgkin's disease (HD) before, during and at different time intervals after cessation of therapy. All patients were in pathological stage I and II following explorative laparatomy with splenectomy. The increase in antibody response was compared to the findings in 12 healthy volunteers with the aim of establishing the optimal time for vaccination. Serum antibodies against 6 of the pneumococcal polysaccharide antigens (types 1, 4, 7F, 14, 18C and 23F) contained in the vaccine were determined by an ELISA. Antibody response to pneumococcal type antigens was similar in healthy adults and in patients with early stage HD before therapy. After treatment, postvaccination antibody response became negligible. Even up to 7 years after cessation of therapy patients were not able to raise a significant antibody response.     

Avascular osteonecrosis in patients treated for Hodgkin's disease

Abstract: The aim of this study is to assess the risk of avascular osteonecrosis (AVN) of the femoral head in patients treated for Hodgkin's disease (HD), in relation to the type of treatment they have received. For this purpose, a cohort of 1391 patients treated for HD at University of Rome between 1972 and 1996 was divided into 2 groups according to their initial treatment. The first group contained 784 patients treated, at the onset of HD, either with chemotherapy (CT) containing steroids, combined in some cases with subdiaphragmatic radiotherapy (RT), or with subdiaphragmatic RT combined with CT without steroids. The second group was made up of 607 patients who had received, initially, supradiaphragmatic RT alone or supradiaphragmatic RT combined with CT without steroids. For the purpose of this study, only the 784 patients belonging to the first group were observed for the appearance of AVN, which occurred in 9 cases. The period of time which elapsed between the end of treatment and the radiological evidence of AVN ranged from 23 to 97 months, with an average of 35 months. Because the number of cases of AVN was so small, the pathogenesis of this complication could not be identified.     

Clinical features and response to treatment of infradiaphragmatic Hodgkin's disease

Among 247 patients with Hodgkin's disease, initial disease presentation was restricted to infradiaphragmatic sites in 17 (6.9%). Advanced age, B symptoms, increased ESR, low lymphocyte and platelet counts, as well as advanced pathological stage and lymphocyte depletion histology were common presenting features of these patients. 7 patients with infradiaphragmatic disease had isolated involvement of inguinofemoral nodes ("peripheral" group) and 10 had only intraabdominal disease ("central" group). Clinical characteristics of patients with "central" forms were different from those with supradiaphragmatic disease, but no differences were observed between "peripheral" infradiaphragmatic and supradiaphragmatic groups. Complete remission was achieved in the 82.2% of patients with infradiaphragmatic disease. Overall survival was 68% at 5 years, and disease-free survival was 74%. No statistically significant differences were observed in complete remission rates, survival, and disease-free survival when supradiaphragmatic, "central" infradiaphragmatic and "peripheral" infradiaphragmatic forms were compared.     

Transient reversal of bone marrow aplasia associated with lymphocyte depleted Hodgkin's disease after combination chemotherapy

This report describes a patient with lymphocyte depleted Hodgkin's disease who presented with bone marrow aplasia. The aplastic marrow reverted to normal after initiation of MOPP chemotherapy; however, 4 months after completion of therapy, bone marrow aplasia recurred in the absence of recurrent Hodgkin's disease. The patient remains free of Hodgkin's disease 34 months after completion of chemotherapy. Bone marrow abnormalities in Hodgkin's disease are reviewed and the current understanding of the pathological mechanisms leading to aplastic anemia is discussed.     

Study of HLA antigens in patients with Hodgkin's disease

This paper studies relations of 21 HLA antigens of the A and B loci to selected characteristics in a group of patients with Hodgkin's disease. The investigated characteristics are age, sex, histological patterns, clinical stage and symptomatology. The considered group consists of 68 patients, 37 males and 31 females aged from 19 to 66 years and from 26 to 63 yr, respectively. A comparison between antigen frequencies for patients and controls (301 unrelated blood donors) is carried out. The results confirm that there is no relation between HLA antigens and Hodgkin's disease. A significant increase of A11 is found for females under 40 yr. Certain HLA antigens show significant correlation neither with the patient age nor with clinical or histological stages. A significant increase of B5 is observed for 16 relapsed patients. For them, significant test characteristics are found in the presence of cross-reacting HLA-B5, B35.     

Displacement of T Lymphocytes with the ‘Helper/Inducer’ Phenotype from Peripheral Blood to Lymphoid Organs in Untreated Patients with Hodgkin's Disease

A panel of previously characterized monoclonal antibodies: B67.6, OKT3, OKT4, B53.4, Leu3a, OKT8, Leu2a, OKM1, M12 and B52.1 were used as a probe to assess mononuclear cells in peripheral blood (PB), lymph nodes (LN) and spleens of untreated patients with Hodgkin's disease (HD). The mean % and absolute number of T lymphocytes were significantly decreased in PB of HD patients when compared with control values. Reduction of circulating T lymphocytes reflected the selective loss of cells showing the ‘helper/inducer’ (‘H/I’) phenotype. In fact, a lower number of these cells was demonstrated in HD patients with advanced disease and, even though to a lesser extent, in those with localized disease. In contrast, decreased values of T cells with the ‘cytotoxic/syppressor’ (‘C/S’) phenotype were only found in patients with advanced disease, showing pan-lymphocytopenia. Unlike PB, LN and spleens involved by HD usually showed increased %s of T lymphocytes, especially of those possessing the ‘H/I’ phenotype. The displacement of T lymphocytes with ‘H/I’ phenotype from PB to lymphoid organs further supports the possibility of a chronic immune response against abnormal cells or unknown antigens in the affected organs of patients with HD.     

Natural killer cell activity in Hodgkin's disease patients undergoing radiation therapy or chemotherapy and radiation therapy

Natural killer (NK) cell activity in peripheral blood mononuclear cells (PBMCs) from patients with Hodgkin's disease was studied using 4 h ⁵¹Cr release assay and K562 cells as sensitive targets. PBMCs were obtained from 15 previously untreated patients at different stages of their disease. PBMCs were also obtained from 46 patients treated by radiation therapy or combined chemotherapy and radiation therapy. Twenty healthy age-matched volunteer donors were used as controls to the treated patients. For these normal donors the mean cytotoxicity was 24.8 ± 5.67% at a 100:1 effector-target cell ratio; and 43.7 ± 12.1% for the treated cancer patients. Fifteen healthy age-matched volunteer donors were used as controls to the untreated patients. The mean cytotoxicity for these normal donors was 20.8 ± 3.61% at a 100:1 effector-target cell ratio; and 37.6 ± 6.65% for the previously untreated cancer patients. The mean cytotoxicity for all 35 normal donors was 23.1 ± 5.22% at a 100:1 effector-target cell ratio. Most treated patients (93.5%) had a complete response to therapy and a significant difference was found between the mean cytotoxicity of the whole group (46 treated patients), compared with controls (P < 0.001). A significant difference (P < 0.05) was also observed when the same 11 patients were studied before and after treatment.     

大骨节病患者淋巴细胞亚群及sIL-2R的检测意义

目的　探讨大骨节病患者外周血淋巴细胞分布形式、血清可溶性白细胞介素 - 2受体 (s IL- 2 R)及其与硒的相关性。方法　在大骨节病病区随机选取经 X线和临床检查确诊的大骨节病儿童 ,同时在该病区和非病区分别选取健康儿童作为对照组。采用单克隆抗体 (抗 CD4 ,CD8)免疫细胞组化法检测淋巴细胞亚群。s IL- 2 R的测定采用双抗体夹心 EL ISA法。结果　大骨节病病区儿童外周血单核细胞 (PBMC)中 CD4 +、CD8+率显著低于非病区水平 (P <0 .0 5 ) ,CD4 / CD8各组间没有差异 (P >0 .0 5 )。患儿组血清 s IL- 2 R水平显著高于非病区水平 (P =0 .0 38)。病区健康儿童组较非病区有升高趋势 ,但差异无显著意义。另外 ,病区儿童红细胞硒水平仍显著低于非病区 (P <0 .0 0 1)。相关分析表明 ,红细胞硒水平与 CD4 +率呈典型正相关 (r=0 .6 2 5 ,P <0 .0 5 ) ,与血清 s IL-2 R水平则无明显相关关系。结论　大骨节病病区儿童外周血处于一种免疫抑制状态 ,以 CD4 + 、CD8+ 比例的减少尤为明显。硒通过影响 PBMC中 T淋巴细胞亚群的分布形式从而在这种免疫紊乱中发挥了重要作用。建议把血清 s IL - 2 R的测定作为检出大骨节病儿童的一种参考指标。     

Umbilical cord blood transplantation in adults with advanced hodgkin's disease: high incidence of post‐transplant lymphoproliferative disease

We report the outcome of 30 consecutive patients with Hodgkin disease (HD) who underwent single‐unit UCBT. Most (90%) patients had failed previous autologous hematopoietic stem cell transplantation. The conditioning regimens were based on combinations of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin. The cumulative incidence (CI) of myeloid engraftment was 90% [95% confidence interval (C.I.), 74–98%] with a median of 18 d (range, 10–48). CI of acute graft‐versus‐host disease (GvHD) grades II–IV was 30% (95% C.I., 17–44%), while the incidence of chronic GVHD was 42% (95% C.I., 23–77%). The non‐relapse mortality (NRM) at 100 d and 4 yr was 30% (95% C.I., 13–46%) and 47% (95% C.I., 29–65%), respectively. EBV‐related post‐transplant lymphoproliferative disease (EBV‐PTLD) accounted for more than one‐third of transplant‐related death, with an estimate incidence of 26% (95% C.I., 9–44). The incidence of relapse at 4 yr was 25% (95% C.I., 9–42%). Four‐year event‐free survival (EFS) and overall survival (OS) were 28% and 30%, respectively. Despite a high NRM and an unexpected high incidence of EBV‐PTLD, UCBT in heavily pretreated HD patients is an option for patients lacking a suitable adult donor, provided the disease is not in refractory relapse.     

Effects of peripheral lymphocyte subpopulations and the clinical correlation with Parkinson's disease

Aim: To understand the characteristics of peripheral immunity in patients with Parkinson's disease (PD), we investigated the natural killer (NK) cell activity and lymphocyte subpopulations including regulatory T (Treg) cells and type 17 helper T (Th17) cells. Methods: Peripheral blood was collected from 29 PD patients (mean age 70.4 years) and 30 healthy controls (mean age 68.9 years). NK cell activity was measured by a calcein acetoxymethyl ester release assay using NK‐sensitive K562 cells, peripheral NK cells and lymphocytes subsets were analyzed using flow cytometry techniques. Results: Comparison of the two groups demonstrated that the percentage of NK cells increased and that of helper T cells, particularly type 1 (Th1), decreased in patients with PD. There was no evidence of Th1/Th2 or Treg/Th17 cell predominance in PD. Moreover, the increase of NK cells and the decrease of Th1 cells correlated with Unified Parkinson's Disease Rating Scale scores and the heart‐to‐mediastinum ratios based on myocardial ¹²³I‐metaiodobenzylguanidine uptake, both of which represent disease severity in patients with PD. Conclusion: Our investigation indicates that a certain proportion of NK cells and other lymphocytes in the peripheral blood of patients with PD and their association with disease severity may reflect the effect of innate immunity in patients with PD in addition to the effect of dopaminergic‐related agents. Geriatr Gerontol Int 2012; 12: 102–107.     

Prognostic factors in Hodgkin's disease stage III with special reference to tumour burden

143 patients with Hodgkin's disease stage III (65 PS III, 78 CS III) were treated with radiotherapy alone (33 patients), combination chemotherapy alone (56 patients), or radiotherapy plus combination chemotherapy (54 patients). They were followed till death or from 7 to 191 months. Prognostic factors including treatment, peripheral + intrathoracic tumour burden (assessed by combining tumour size in each involved region with number of involved regions), intraabdominal tumour burden (assessed by combining size of lymphographically involved lymph nodes in each region with number of lymphographically involved regions), histologic subtype, B-symptoms, number of involved regions, mediastinal involvement, pretreatment ESR, sex, age, laparotomy, and substage were examined in multivariate analysis. With regard to disease-free survival, total tumour burden (intraabdominal and peripheral + intrathoracic) emerged as the only pre-treatment factor of independent prognostic significance. With regard to overall survival the only factor of independent significance apart from age turned out to be intraabdominal tumour burden. The results of the present study thus support recently published findings regarding early stage disease to the effect that tumour burden is the single most important prognostic factor in Hodgkin's disease.     

Changes in bone marrow and peripheral blood lymphocyte subset findings with onset of hepatitis-associated aplastic anemia

Rationale:Hepatitis-associated aplastic anemia (HAAA) is a rare illness that results in bone marrow failure following hepatitis development. The etiological agent remains unknown in most HAAA cases. However, clinical features of the disease and immunotherapy response indicate that immune-mediated factors play a central role in the pathogenesis of HAAA. Activation of cytotoxic T cells and increase in CD8 cells could exert cytotoxic effects on the myelopoietic cells in the bone marrow.Patient concerns:A 15-month-old boy was brought to our hospital with complaints of generalized petechiae and purpura observed a week prior to hospitalization. His liver was palpated 3 cm below the costal margin, platelet count was 0 × 10⁴/μL, and alanine aminotransferase level was 1346 IU/L. A blood test indicated cytomegalovirus infection, and 3 bone marrow examinations revealed progressive HAAA. As the disease progressed to the 3^rd, 6^th, and 9^th week after onset, CD4⁺ T cells were markedly decreased, CD8⁺ T cells were markedly increased, and the CD4/CD8 ratio was significantly decreased. The number of B cells and natural killer cells decreased with time, eventually reaching 0.0%.Diagnosis:HAAA.Interventions:Rabbit antithymocyte globulin and eltrombopag olamine (a thrombopoietin receptor agonist) were administered.Outcomes:The patient''s platelet count returned to normal, and bone marrow transplantation was avoided. The peripheral blood lymphocytes (PBLs) improved as the patient''s general condition recovered.Lessons:This case demonstrates that HAAA induced by cytomegalovirus infection features decreasing CD4⁺ and increasing CD8⁺ PBLs as the bone marrow hypoplasia progresses. The PBLs return to their normal levels with the recovery from the disease. Our case findings thus support the involvement of immunological abnormality in HAAA.     

Long-term results of 60 patients with pathologic stage I & IIA Hodgkin's disease treated with exclusive mantle radiation therapy.

Between January 1972 and December 1982 60 patients with pathological stage IA and IIA Hodgkin's disease (HD) were submitted to Mantle irradiation only. Twenty-five were in stage I (32.1%) and 35 in stage II (67.9%). All patients were submitted to staging laparotomy. Cases with large mediastinal mass were excluded from this series. Delivered doses were 44 Gy in involved areas, 40 Gy on the mediastinum and 36 Gy on uninvolved sites. Twenty-four patients in stage I (96%) and 33 in stage II (94.2%) obtained complete remission. Actuarial 10- and 20-yr overall (OS) rates were 86% and 79.1%, respectively. Event-free (EFS) and relapse-free (RFS) survival rates at 10 and 20 yr were 67.5% and 62.1%, respectively. The occurrence of disease relapse resulted in the only statistical significant prognostic factor for OS in both univariate and multivariate analysis. Distant and extranodal recurrences were significantly (P<0.01) related to a reduced OS. On multivariate analysis stage was the only determinant factor for increased RFS. Extended field RT proved to be an effective curative modality for stage I HD patients, whereas 15 out of 33 patients in stage II relapsed requiring salvage therapy. Long-term analysis of survival and treatment-related morbidity rates will improve our knowledge and assist the physicians to choose the therapeutic option to offer to HD patients.     

不同免疫状态慢性HBV感染患者的T淋巴细胞及NKG2D表达差异研究

目的探讨慢性HBV感染者在不同免疫状态下的T淋巴细胞及自然杀伤细胞G2D(NKG2D)表达差异。方法根据免疫状态的不同将80例慢性HBV感染患者分为免疫耐受组(28例)、免疫清除组(30例)、低(非)复制组(22例),另选取30名健康体检者作为对照组。对4组研究对象进行外周血T淋巴细胞亚群、NK细胞、NKG2D细胞频率及血清肿瘤坏死因子-α(TNF-α)、γ干扰素水平检测。结果4组研究对象的CD3^+T淋巴细胞百分比,差异均无统计学意义(P>0.05)。免疫清除组的CD4^+T淋巴细胞、CD4^+/CD8^+、NK细胞百分比分别为(30.14±5.36)%、(1.10±0.33)%、(9.67±4.31)%,均显著低于另外三组,CD8^+T淋巴细胞、NKG2D+/NK细胞百分比分别为(33.56±5.37)%、(12.96±3.42)%,均显著高于另外三组(P<0.05)。免疫耐受组和低(非)复制组的NKG2D^+/NK细胞百分比分别为(3.46±1.15)%和(3.55±1.07)%均显著低于对照组,免疫清除组的NKG2D+/NK细胞百分比显著高于对照组(P<0.05)。免疫清除组的TNF-α、γ干扰素水平分别为(69.62±16.46)ng/L和(69.85±12.30)ng/L,均显著高于免疫耐受组、低(非)复制组及对照组(P<0.05)。免疫耐受组、低(非)复制组及对照组的TNF-α、γ干扰素水平比较,差异均无统计学意义(P>0.05)。结论慢性HBV感染患者在不同免疫状态下,外周血淋巴细胞及NKG2D细胞表达有明显差异,临床可通过测定HBV感染者外周血T淋巴细胞、NKG2D细胞水平来评估患者的免疫状态,指导临床治疗。     

Rectal Epstein-Barr virus-positive Hodgkin's lymphoma in a patient with Crohn's disease: Case report and review of the literature

We present the case of a 35-year-old man with Crohn's disease diagnosed at the age of 27, several months after an operation for small-bowel adenocarcinoma. Seven years after the adenocarcinoma diagnosis, the patient presented with severe continuous anal pain and diarrhea. In parallel with antibiotic administration, the patient was given treatment with Infliximab, but without clinical symptom amelioration. Sigmoidoscopy and subsequent biopsies from an ulcerated rectal area supported the diagnosis of Epstein-Barr virus-positive (EBV(+)) primary Hodgkin's lymphoma. Infliximab administration was immediately discontinued and the patient underwent oncological follow-up and began a course of chemotherapy. Only a few cases with primary gastrointestinal Hodgkin's lymphoma in Crohn's disease patients have so far been reported, including a variety of scenarios on the causal relationship including disease duration, presence of EBV, long-term immunosuppressive treatment and, recently, anti-TNFα administration.     

Treatment response and colonic gene expression in patients with Crohn's disease

Objective. Responses and adverse events to medication vary greatly among patients with Crohn's disease (CD). The aim of this study was to investigate whether global gene expression profiles could predict such responses and possible side effects. Material and methods. Tissue specimens from the descending colon were obtained from 32 CD patients (in 18 patients from areas without inflammation and in 14 patients from inflamed areas). Gene profiling was done using the Affymetrix Human Genome U133 Plus 2.0 GeneChip array. Hybridization data were analyzed with dChip software. Results. There were no differentially expressed genes between six patients who responded well to azathioprine and four who did not. No differences were found between 12 patients with adverse events to azathioprine and 9 patients who tolerated this drug. Sixteen patients who were not glucocorticoid-dependent had no differentially expressed genes as compared with 15 glucocorticoid-dependent patients. Six patients who responded well to infliximab had only one differentially expressed gene as compared to four patients who did not. Conclusions. DNA microarray analyses did not show differentially expressed genetic profiles from colonic mucosal cells obtained from groups of patients classified according to therapeutic criteria.     

Correlation of blood lymphocyte CTLA-4 (CD152) induction in Hodgkin's disease with proliferative activity,interleukin 2 and interferon-gamma production

Expression of the downregulatory CTLA-4 molecule was determined on unstimulated and anti-CD3 + recombinant interleukin 2 (rIL-2)-stimulated peripheral blood T cells in Hodgkin's disease (HD) and correlated with the T-cells' proliferative activity, IL-2 and interferon (IFN)-gamma production. There was a negligible percentage of CTLA-4+/CD3+ cells before culture. The mean percentage of CTLA-4+/CD3+ lymphocytes increased gradually, peaked after 72 h of stimulation and returned to basal values after 96 h of stimulation. The mean proportion of CTLA-4+/CD3+ cells from untreated patients was significantly higher after 24, 48 and 72 h of stimulation compared with controls. The mean percentage of CTLA-4+/CD3+ cells from patients in clinical remission (CR) was lower than that of untreated patients, but remained significantly higher compared with controls. Lymphocytes from untreated HD patients showed impaired proliferative activity, IL-2 and IFN-gamma production compared with controls. The proliferative activity of the lymphocytes, IL-2 and IFN-gamma production remained significantly lower in CR compared with controls. The proportion of CTLA-4+/CD3+ cells negatively correlated with proliferative activity, IL-2 and IFN-gamma production in HD patients and controls. However, some untreated patients as well as patients in CR with normal mean fluorescence intensity values of CTLA-4 showed unimpaired T-cell function tests. Our study provides the first evidence of an increased expression of downregulatory CTLA-4 molecule on stimulated T-cells in HD, which could be one of the mechanisms of immune deficiency in this disease.     

Five genetic markers in the interleukin 1 family in relation to inflammatory bowel disease

Background—An imbalance between theproinflammatory cytokine interleukin 1β (IL-1β) and theanti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra) has beenpostulated as a pathogenic factor in inflammatory bowel disease (IBD).
Aims—To study allelic frequenciesof novel polymorphisms in the genes for IL-1β and IL-1ra in patientswith IBD and to assess the relation between ex vivo cytokine productionand allelic variants of the IL-1β and IL-1ra genes.
Subjects—Two hundred and seventyhealthy controls, 74 patients with ulcerative colitis (UC), 72 withCrohn's disease (CD), 40 with primary sclerosing cholangitis for theallelic frequencies, and 60 healthy individuals for the ex vivostimulation test.
Methods—Genotyping was performed bypolymerase chain reaction and subsequent cleavage with specificendonucleases (Mwo1, MspAI1, Alu1, Taq1, BsoF1) for five novelrestriction fragment length polymorphisms (RFLPs) in the genes forIL-1ra and IL-1β.
Results—No significant differences were found inthe allelic frequencies or allele carriage rates of the markers in theIL-1β and IL-1ra genes between CD, UC, and healthy controls. Noassociation between the genetic markers and cytokine production levelswas observed. Patients with UC carried the combination of both the infrequent allele of the Taq1 RFLP and the Mwo1 RFLP significantly morefrequently (35.2% in UC versus 71.1% in controls).
Conclusions—UC is associatedwith carriage of both infrequent alleles of the Taq1 and Mwo1 RFLPs.However, it could not be confirmed whether the association reflects apathogenic mechanism underlying UC.