Desensitization protocol in highly HLA-sensitized and ABO-incompatible high titer kidney transplantation

Background

A positive crossmatch indicates the presence of donor-specific alloantibodies and is associated with a graft loss rate of >80%; anti-ABO blood group antibodies develop in response to exposure to foreign blood groups, resulting in immediate graft loss. However, a desensitization protocol for highly HLA-sensitized and ABO-incompatible high-titer kidney transplantation has not yet been established.

Methods

We treated 6 patients with high (≥1:512) anti-A/B antibody titers and 2 highly HLA-sensitized patients. Our immunosuppression protocol was initiated 1 month before surgery and included mycophenolate mofetil (1 g/d) and/or low-dose steroid (methylprednisolone 8 mg/d). Two doses of the anti-CD20 antibody rituximab (150 mg/m²) were administered 2 weeks before and on the day of transplantation. We performed antibody removal with 6–12 sessions of plasmapheresis (plasma exchange or double-filtration plasmapheresis) before transplantation. Splenectomy was also performed on the day of transplantation. Postoperative immunosuppression followed the same regimen as ABO-compatible cases, in which calcineurin inhibitors were initiated 3 days before transplantation, combined with 2 doses of basiliximab.

Results

Of the 8 patients, 7 subsequently underwent successful living-donor kidney transplantation. Follow-up of our recipients showed that the patient and graft survival rates were 100%. Acute cellular rejection and antibody-mediated rejection episodes occurred in 1 of the 7 recipients.

Conclusions

These findings suggest that our immunosuppression regimen consisting of rituximab infusions, splenectomy, plasmapheresis, and pharmacologic immunosuppression may prove to be effective as a desensitization protocol for highly HLA-sensitized and ABO-incompatible high-titer kidney transplantation.     

Pilot study of radiofrequency ablation (RFA) therapy in patients with early breast cancer

A recent breast cancer operation appears to have become more simplified, and we may cure an early stage breast cancer without a surgery in the future. This study was approved by our institutional review board and all patients received the study information. We started a radiofrequency ablation (RFA) in April 2008 for breast cancer patients without extensive ductal spreads and the tumor size of 2 cm or less measured by magnetic resonance imaging (MRI). At first, we performed five patients from a clinical viewpoint of technique and safety. All cases were performed safely. There was no complication such as burns. At the mid observation period of 22 months in average (range 21-24), no local recurrence and distant metastases were occurred after RFA. Cosmetic after RFA was excellent in all cases.     

Usefulness of (18)F-FDG positron emission tomography/computed tomography for the diagnosis of pyothorax-associated lymphoma: A report of three cases

Pyothorax-associated lymphoma (PAL) is a unique and rare non-Hodgkin's lymphoma developing in the pleural cavity following a long-standing history of chronic pyothorax (CP). The development of F-18 2'-deoxy-2fluoro-D-glucose (FDG) positron emission tomography combined with computed tomography (PET/CT) has contributed to the evaluation of lymphoma staging. However, only a few studies describing FDG-PET/CT findings in PAL have been published. This study reported three cases of PAL; all 3 patients had previously undergone artificial collapse therapy for pulmonary tuberculosis. Both the first case (an 84-year-old male) and second case (an 83-year-old male) complained of abdominal pain. An ultrasound scan revealed a mass shadow in the left chest wall without abnormal findings in the abdomen, and the CT and magnetic resonance imaging scans suggested malignant lymphoma of the left chest. FDG-PET/CT imaging showed extremely intense FDG uptake only in the left pleura and chest wall. Diagnosis was CP in the two patients, showing a high maximum standardized uptake value (SUVmax: early, 14.8 and delayed, 19.4 in the first case; early, 20.8 and delayed, 27.3 in the second case, respectively). Histopathological analysis of the specimens obtained by biopsy of the PET/CT-positive pleural mass showed non-Hodgkin's, diffuse large B cell lymphoma in the two cases. The third case was a 79-year-old male with relapse after right pleuropneumonectomy for PAL (diffuse large B cell lymphoma) 4 years earlier. PET/CT showed intense FDG uptake (SUVmax: early, 19.9 and delayed, 35.7) in the right pleura and chest wall. Diagnosis was CP, suggesting the recurrence of PAL. Furthermore, abnormal intense FDG uptake was noted in the hilar, mediastinal and supraclavicular lymph nodes, as well as in the spleen. In conclusion, FDG-PET/CT imaging is useful in the evaluation of the area of invasion in PAL.     

Effects of ezetimibe add-on therapy for high-risk patients with dyslipidemia

Background  

Ezetimibe (Zetia^?) is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia. Statin, an inhibitor of cholesterol synthesis, is the first-choice drug to reduce low-density lipoprotein-cholesterol (LDL-C) for patients with hypercholesterolemia, due to its strong effect to lower the circulating LDL-C levels. Because a high dose of statins cause concern about rhabdomyolysis, it is sometimes difficult to achieve the guideline-recommended levels of LDL-C in high-risk patients with hypercholesterolemia treated with statin monotherapy. Ezetimibe has been reported to reduce LDL-C safely with both monotherapy and combination therapy with statins.     

Phosphorylation of Crk on tyrosine 251 in the RT loop of the SH3C domain promotes Abl kinase transactivation

Here, we report the identification and characterization of a novel tyrosine phosphorylation site in the carboxy-terminal Src Homology 3 (SH3) (SH3C) domain of the Crk adaptor protein. Y251 is located in the highly conserved RT loop structure of the SH3C, a region of Crk involved in the allosteric regulation of the Abl kinase. Exploiting kinase assays to show that Y251 is phosphorylated by Abl in vitro, we generated affinity-purified antisera against phosphorylated Y251 in Crk and showed that Abl induces phosphorylation at Y251 in vivo, and that the kinetics of phosphorylation at Y251 and the negative regulatory Y221 site in vitro are similar. Y251 on endogenous Crk was robustly phosphorylated in chronic myelogenous leukemia cell lines and in A431 and MDA-MB-468 cells stimulated with epidermal growth factor. Using streptavidin-biotin pull downs and unbiased high-throughput Src Homology 2 (SH2) profiling approaches, we found that a pY251 phosphopeptide binds specifically to a subset of SH2 domains, including Abl and Arg SH2, and that binding of pY251 to Abl SH2 induces transactivation of Abl 1b. Finally, the Y251F Crk mutant significantly abrogates Abl transactivation in vitro and in vivo. These studies point to a yet unrealized positive regulatory role resulting from tyrosine phosphorylation of Crk, and identify a novel mechanism by which an adaptor protein activates a non-receptor tyrosine kinase by SH2 domain displacement.     

Mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits

The coexistence of hypertension and hypercholesterolaemia from youth may increase the prevalence of and mortality from cardiovascular disease and stroke. We thus investigated haemodynamics of mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits aged 10-12 months old, as models of heritable hypercholesterolaemia. Pressure and flow waves were simultaneously recorded at the ascending aorta with a catheter-tip micromanometer and ultrasonic flow meter under pentobarbital anaesthesia, respectively. Systolic (119.3 +/- 6.5 and 138.4 +/- 7.4 mmHg (mean +/- SD) for control and KHC rabbit groups; p < 0.001), diastolic (95.7 +/- 6.1 and 109.8 +/- 5.2; p < 0.001), mean (105.8 +/- 6.5 and 122.5 +/- 4.9; p < 0.001) and pulse (23.7 +/- 2.5 and 28.6 +/- 4.0; p < 0.001) pressures as well as total peripheral vascular resistance (0.32 +/- 0.02 and 0.37 +/- 0.03 mmHg/ml/min; p < 0.001) were significantly greater in the KHC rabbit group than those in the age-matched control rabbit group, respectively, while there were no significant differences in the mean aortic flow, heart rate or stroke volume between the two rabbit groups. Aortic input impedance (p < 0.05) and reflection coefficient (p < 0.05) were significantly greater at lower frequency in the KHC rabbit group than in the control rabbit group, whereas there was no significant difference in the characteristic impedance between the two rabbit groups. Plasma angiotensin I (p < 0.01) and II (p < 0.01) levels and serum angiotensin converting enzyme activity (p < 0.05) were significantly greater in the KHC rabbit group than in the age-matched control rabbit group. Atheromatous plaque was in the early stage and composed mainly of abundant foam cells. Neither sclerotic lesions nor stenosis were observed in main peripheral arteries. The mild hypertension in young KHC rabbits was due partly to the increased activity of the renin-angiotensin system. These findings may be thought provoking in elucidating the mechanism and developing preventive and therapeutic strategies in young patients with coexistent hypertension and hypercholesterolaemia.