Effective treatment of a mouse model of Sjögren's syndrome with eyedrop administration of anti-CD4 monoclonal antibody

OBJECTIVE: To determine whether eyedrop administration of an anti-CD4 monoclonal antibody (mAb) is effective in the treatment of Sj?gren's syndrome (SS) using a mouse model of the disease. METHODS: The anti-CD4 mAb was administered daily into the eyes of mice with SS from ages 4 to 8 weeks or ages 10 to 12 weeks. During treatment, tear volume was monitored and after final treatment, histologic features of the lacrimal and salivary glands, the phenotypes and function of T cells, and serum titers of anti-alpha-fodrin antibody were examined. RESULTS: Eyedrop administration of anti-CD4 mAb before the onset of SS prevented the autoimmune pathology seen in the lacrimal glands but not that in the salivary glands. Furthermore, eyedrop administration of anti-CD4 mAb after the development of SS inhibited mononuclear cell infiltration and the destruction of parenchyma only in the lacrimal glands. Eyedrop administration of anti-CD4 mAb suppressed the local activation of CD4+ T cells rather than deleting CD4+ T cells, which reduced the expansion of pathologic CD4+ T cells against alpha-fodrin. CONCLUSION: These results demonstrate the remarkable efficacy of anti-CD4 mAb eyedrops in the treatment of SS eye symptoms, which illustrates a new antibody-based therapeutic strategy for patients with eye problems caused by SS as well as other diseases.     

The additive effect ofα-difluoromethylornithine (DFMO) and radiation therapy on a rat glioma model

Summary The effects of -difluoromethylornithine (DFMO), radiation and the therapy of their combination were investigated in rats bearing G-XII glioma. DFMO treatment as well as radiation therapy prolonged the survival period when compared to the results in non-treated control rats. The combination therapy showed a greater effect on the survival rate than the single therapies, the effect being additive. The concentration of putrescine, spermidine, andN ¹-acetylspermidine in tumor tissues was lowered by DFMO, while that of spermine was slightly elevated. Radiation decreased the concentration of all the polyamines, putrescine, spermidine, spermine andN ¹-acetylspermidine. The concomitant treatment with DFMO and radiation further decreased the concentrations of putrescine andN ¹-acetylspermidine in tumor tissues. The survival period of glioma-bearing rats is inversely correlated with the tissue levels of putrescine plusN ¹-acetylspermidine.Abbreviations DFMO -difluoromethylornithine - BrdUrd bromodeoxyuridine     

Radioimmunodetection of residual, recurrent or metastatic germ cell tumors using technetium-99 anti-(α-fetoprotein) Fab′ fragment

Purpose: The majority of patients with germ cell tumors are cured by multimodality therapy that consists of cisplatin-based chemotherapy and/or surgical resection. Serum tumor markers and conventional radiographs are utilized to stratify patients into treatment categories. Efforts to individualize chemotherapy or minimize surgical interventions without compromising outcome are important. Immunomedics (Morris Plains, New Jersey) developed an anti-(α-fetoprotein) (anti-AFP) monoclonal antibody IMMU-30 labeled with 15–20 mCi technetium-99, and the purpose of this study is to determine the sensitivity and specificity of radio-immunoscintigraphy using ^99mTc anti-AFP antibody for the diagnosis of active germ cell tumors. Methods: A group of patients with germ cell tumors were enrolled in a non-prospective fashion and 48 AFP scans using ⁹⁹Tc anti-AFP Fab′ fragment were obtained. At the time of the AFP scan, serum AFP was elevated in 40 measurements with a median level of 21 ng/ml (1.6–66, 210.0 ng/ml). AFP scans were obtained at the initial staging, during treatment, at relapse or at long-term follow-up and compared with conventional radiographs done within 4 weeks of the AFP scans. Results: An overall diagnostic sensitivity of 89% and specificity of 58% were obtained. Conclusions: AFP scanning appears useful and to be sufficiently sensitive to justify prospective studies comparing the procedure with conventional imaging. Received: 19 July 1999 / Accepted: 24 September 1999     

Alemtuzumab (anti-CD52 monoclonal antibody) as single-agent therapy in patients with relapsed/refractory chronic lymphocytic leukaemia (CLL)—a single region experience on consecutive patients

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is used in patients with refractory chronic lymphocytic leukaemia (CLL). We report results in health care with alemtuzumab on consecutive, advanced-stage patients from a well-defined geographical region. Records from 1,301 patients (Stockholm-Cancer-Registry 1991–2010) identified 56 relapsed/refractory patients treated with alemtuzumab. Median age was 69 years, 88 % had advanced Rai-stage with median 3 prior therapies. One fourth had bulky lymphadenopathy and 73 % were refractory to purine analogues. Median treatment length was 11.6 weeks. Median cumulative dose was 930 mg, significantly higher (p?=?0.0277) for responders. Overall response-rate (ORR) was 43 %; 32.5 %, 50 % and 87.5 % in the Refractory, Purine analogue relapsed and Relapsed/Other subgroup, respectively. Response rate was significantly associated with subgroup (p?=?0.0104). Good performance status (PS) was associated with better response rate (p?=?0.0227). Median time-to-treatment-failure (TTF) (months) was 7.8 months, significantly (p?p?p?=?0.0038). Twenty percent were retreated with alemtuzumab with an ORR of 54.5 %, and a TTF of 7.1 months. A high cumulative dose/longer duration of therapy and a relatively high response rate was observed compared to previous reports. Optimal patient identification and management may result in avoidance of early discontinuation and possibly better outcomes.     

Damage control with abdominal vacuum therapy (VAC) to manage perforated diverticulitis with advanced generalized peritonitis—a proof of concept

Purpose

Perforated diverticulitis with advanced generalized peritonitis is a life-threatening condition requiring emergency operation. To reduce the rate of colostomy formation, a new treatment algorithm with damage control operation, lavage, limited closure of perforation, abdominal vacuum-assisted closure (VAC; V.A.C.®), and second look to restore intestinal continuity was developed.

Methods

This algorithm allowed for three surgical procedures: primary anastomosis ± VAC in stable patients (group I), but damage control with lavage, limited resection of the diseased colonic segment, VAC and second-look operation with delayed anastomosis in patients with advanced peritonitis or septic shock (group II), and Hartmann procedure was done for social reasons in stable patients (group III)

Results

All 27 consecutive patients (16 women; median age 68 years) requiring emergency laparotomy for perforated diverticulitis (Hinchey III/IV) between October 2006 and September 2008 were prospectively enrolled in the study. No major complications were observed in group I (n?=?6). Nine patients in group II (n?=?15) had intestinal continuity restored during a second-look operation, of whom one patient developed anastomotic leakage. The median length of stay at intensive care unit was 5 days. Considering an overall mortality rate of 26% (n?=?7), the rate of anastomosis in surviving patients was 70%.

Conclusions

Damage control with lavage, limited bowel resection, VAC, and scheduled second-look operation represents a feasible strategy in patients with perforated diverticulitis (Hinchey III and IV) to enhance sepsis control and improve rate of anastomosis.     

Reevaluation of predictive value of ACL and anti-β2GP1 antibody for thrombosis in patients with systemic lupus erythematosus: from a perspective of a practical world

Detection of ACL (anticardiolipin, ACL) and anti-??2GP1 (beta2 glycoprotein1, ??2GP1) antibody has been widely used, and the criteria of APS (Antiphospholipid syndrome, APS) have been used for the prediction of thrombosis in patients with SLE. What is the exact predictive value of these two antibodies? Is it really necessary to apply the criteria of APS to each patient just for the purpose of prediction of thrombosis? The aim of this retrospective study is to reevaluate the predictive value of different combination of ACL and anti-??2GP1 antibody for thrombosis formation in Chinese patients with SLE. Patients fulfilling the 1997 ACR classification criteria for SLE were enrolled and retrospectively analyzed. Thrombosis was confirmed by ultrasound, cerebral MRI, computed tomography pulmonary angiogram and angiography. Both IgG and IgM isotype of ACL and anti-??2GP1 antibody were detected with ELISA kit. ROC curves and other parameters of diagnostic test for different combination of ACL and anti-??2GP1 were analyzed and compared. 175 patients were recruited and thrombosis was diagnosed in 49 patients. In patients with thrombosis, 95.9% had been treated with glucocorticoids before detection of the two antibodies, 44.9% had hypertension and 53.1% had hyperlipidemia. ACL was positive in 28 patients (16%), and anti-??2GP1 antibody was positive in 21 patients (12%). The presence of a low or higher titer of either ACL (>12?RU/ml) or anti-??2GP1 antibody (>20?RU/ml) once has the highest predictive accuracy. The sensitivity, the specificity, the Youden??s index and the area under ROC curve are 61.11%, 81.11%, 0.4222 and 0.711 respectively. A transient low or higher titer of ACL or anti-??2GP1 antibody had a good predictive value for thrombosis in patients with SLE, especially in those with other traditional risk factors for thrombosis and those treated with glucocorticoids.     

Infective endocarditis complicating rituximab (anti-CD20 monoclonal antibody) treatment in an SLE patient with a past history of Libman–Sacks endocarditis: a case for antibiotic prophylaxis?

We report a 54 year old female whose successful treatment of cerebral lupus with rituximab was complicated by the development of streptococcus intermedius, on valves damaged by Libman-Sacks endocarditis more than 20 years previously.     

Viral and host factors that contribute to efficacy of interferon-α2a therapy in patients with chronic hepatitis C

Using conventional statistical analysis and multiple regression analysis, we investigated the viral and host factors that influence the response to recombinant interferon-_2a therapy in patients with chronic hepatitis C. A total of 36 patients was randomly assigned to three administration schedules, 12 patients in each. Response to treatment was set as the criterion variable. Four variables were statistically significant in the conventional method in predicting a good therapeutic outcome: HCV genotype III and IV, lower histology activity index (HAI) score for liver, higher total dose of interferon administration, and lower serum HCV RNA concentration. In multiple regression analysis, a combination of the above four variables resulted in a higher multiple correlation coefficient (R=0.84,P<0.0001) using a stepwise method. Of those four, HCV genotype had the highest absolute value of standard partial regression coefficient (0.51). The HCV RNA concentration was correlated with HCV genotype and HAI score, whereas HCV genotype and HAI score showed no correlation. Thus, HCV RNA concentration was not statistically significant in multiple regression analysis. These findings indicate that HCV genotype, HAI score, and schedule of administration can be important predictors of the response to interferon therapy.This study was supported by a grant from the Japanese Ministry of Health and Welfare.     

A risk-stratification model based on the initial concentration of the serum monoclonal protein and MYD88 mutation status identifies a subset of patients with IgM monoclonal gammopathy of undetermined significance at high risk of progression to Waldenström macroglobulinaemia or other lymphoproliferative disorders

IgM monoclonal gammopathies of undetermined significance (IgM MGUS) are associated with a risk of progression to Waldenström macroglobulinaemia (WM) or other lymphoproliferative disorders (LPD) of 1–2% per year. We analysed 176 consecutive patients with IgM MGUS to evaluate risk factors for progression. With a median follow-up of 83 months (1214 person-years), 15 patients (8·5%) progressed to WM (n = 14) or marginal zone lymphoma (n = 1). The rate of progression was 1·32% per year (95% confidence interval [CI] 0·80–2·20). The serum monoclonal protein concentration and the MYD88 mutation were independent risk factors for progression (Hazard ratio [HR] 23·3, 95% CI 2·0–273·3, P = 0·012 and HR 24·4, 95% CI 2·2–275·3, P = 0·010, respectively). The cumulative incidence of progression, while considering death as a competing event, was 11·6% at 5 years and 38·0% at 10 years in MYD88-mutated patients with a serum monoclonal protein of 10 g/l or higher, as compared with 0% at 5 years and 1·1% at 10 years for patients with none or one risk factor. This risk-stratification model is able to identify a subset of patients with IgM MGUS at high risk of progression to WM or LPD who deserve a lifelong follow-up.     

Molecular analysis of a patient with type I Glanzmann thrombasthenia and clinical impact of the presence of anti-αIIbβ3 alloantibodies

The occurrence of transfusion-related alloimmunization against αIIbβ3 is a major concern in patients with Glanzmann thrombasthenia (GT). However, few data are available about molecular defects of GT patients with anti-αIIbβ3 alloantibodies as well as clinical impact of these antibodies on platelet transfusion. Here, we report a case of type I GT with anti-HLA and anti-αIIbβ3 alloantibodies, who underwent laparoscopic total gastrectomy due to gastric cancer. We found a novel β3 nonsense mutation, 892C > T (Arg272X), and the patient was homozygous for the mutation. Laparoscopic gastrectomy was successfully performed with continuous infusion of HLA-matched platelet concentrates and bolus injection of recombinant factor VIIa at 2 h intervals. Total bleeding was 370 mL and no red-cell transfusion was necessary. Flow cytometric analysis employing anti-αIIbβ3 monoclonal antibody revealed that the transfused platelet count was maintained around 20–30 × 10⁹/L during the operation and 10 × 10⁹/L on the following day. Flow cytometric analysis also showed that transfused platelets retained normal reactivity to ADP stimulation. These results indicate that flow cytometry is useful to assess survival and function of transfused platelets in GT patients with anti-αIIbβ3 antibodies.     

Thrombolytic effects of a combined therapy with targeted microbubbles and ultrasound in a 6?h cerebral thrombosis rabbit model

Our previous study has shown that P1 polypeptide-loaded microbubbles (clot-targeted microbubbles, TMB) are effective for thrombolysis and recanalization in a 0.5?h cerebral thrombosis rabbit model when combined with low-frequency ultrasound (LFUS, 0.8?MHz). However, the thrombolytic effects of TMB combined with LFUS are still unclear in a 6?h cerebral thrombosis rabbit model, which closely resembles human embolic stroke. Aiming to extend the 3?h therapeutic window limitation of thrombolytic drugs, a 6?h cerebral thrombosis model of common carotid artery (CCA) occlusion was induced in rabbits, and thrombolysis using TMB by intra-arterial (IA) and intravenous (IV) application combined with LFUS was then compared to untargeted microbubbles (UTMB) and recombinant tissue plasminogen activator (rt-PA). The patency score and thrombolysis in brain ischemia (TIBI) in IA TMB combined with LFUS (IA TMB/LFUS) were significantly higher compared to the IA normal saline control with LFUS (IA SC/LFUS) (both P?相似文献   

A Case of Buerger’s Disease Associated with High Levels of Lipoprotein(a)

We describe a 35-year-old man affected by Buerger’s disease in association with very high levels of lipoprotein(a). Received: 9 June 1998 / Accepted: 9 June 1998     

Application of a four antibody (cMPO/cCD79α/cCD3/CD45) combination to the diagnosis of acute leukemia expressing cross-lineage antigens

Objective To explore the diagnostic value of intracellular antibody combination in acute leukemia (AL) expressing cross-lineage cell-surface antigens. Methods Flow cytometric immunophenotyping using intracellular antibody combination (cMPO/eCD79α/cCD3/CD45) was performed additionally in 60 patients who expressed     

An a priori prediction model of response to peginterferon plus ribavirin dual therapy in naïve patients with genotype 1 chronic hepatitis C

BackgroundAim was to select naïve patients with genotype 1 chronic hepatitis C having a high probability of response to Peg-interferon + ribavirin therapy.MethodsIn 1073 patients (derivation cohort), predictors of rapid and sustained virological response were identified by logistic analysis; regression coefficients were used to generate prediction models for sustained virological response. Probabilities at baseline and treatment week 4 were utilized to develop a decision rule to select patients with high likelihood of response. The model was then validated in 423 patients (validation cohort).ResultsIn the derivation cohort, 257 achieved rapid virological response and 818 did not, with sustained virological response rates of 80.2% and 25.4%, respectively; interleukin-28B polymorphisms, fibrosis staging, gamma-glutamyl transferase, and viral load predicted sustained virological response. Assuming a <30% sustained virological response probability for not recommending Peg-interferon + ribavirin, 100 patients (25.6%) in the validation cohort were predicted a priori to fail this regimen. Assuming a ≥80% sustained virological response probability as a threshold to continue with Peg-interferon + ribavirin, 61 patients were predicted to obtain sustained virological response, and 55 of them (90.2%) eventually did.ConclusionsThis model uses easily determined variables for a personalized estimate of the probability of sustained virological response with Peg-interferon + ribavirin, allowing to identify patients who may benefit from conventional therapy.     

Quality assessment of platelets stored in a modified platelet additive solution with trehalose at low temperature (10 °C) and in vivo effects on rabbit model of thrombocytopenia

Trehalose is widely used as a cryoprotective reagent to preserve various cells. Platelet additive solution-III (PAS) has been used to maintain platelet function, benefit the virus inactivation, and extend the storage period. PAS with trehalose (PAS-III M?+?T) may effectively protect platelets (PLTs) at a relatively low temperature (10?°C). The apheresis PLTs from six donors were divided into two groups. Group A was stored in PAS-III M?+?T at 10?°C as experimental group and group B in plasma at 22?°C as control group. The samples were collected on different storage dates, and multiple parameters were determined or investigated for in vitro studies. The in vivo recovery and survival of rabbit PLTs stored in the same conditions, and then labeled with ⁵¹Cr were measured and evaluated using a rabbit model of thrombocytopenia. Over 9 days, P-selectin expression increased significantly in a time-dependent manner in both groups (n?=?6). The levels of the hypotonic shock reaction and PLT aggregation rate decreased in both groups and were significantly higher in group A than B after 1 day of storage. The lactate dehydrogenase (LDH) release and glucose (GLU) consumption increased similarly, but the levels were significantly lower in group A than B. The pH decreased significantly after 5 days of storage in group B but did not change in group A. After 5 days, the morphology of the PLTs in group B maintained a more normal shape than that of group A. The recovery and survival of PLTs stored in both groups were not significantly different (p?>?0.05). The bacteria growth was not examined out in both groups for up to 5 (group A) and 9 (group B) days. Storage of PLTs in the modified PAS at low temperature was more effective in protecting PLT functions than that of standard storage method and may have the potential to decrease the risk of PLT activation and bacterial contamination.