CD48 as a novel molecular target for antibody therapy in multiple myeloma

Monoclonal antibody (mAb) drugs are desirable for the improvement of multiple myeloma (MM) treatment. In this study, we found for the first time that CD48 was highly expressed on MM plasma cells. In 22 out of 24 MM patients, CD48 was expressed on more than 90% of MM plasma cells at significantly higher levels than it was on normal lymphocytes and monocytes. CD48 was only weakly expressed on some CD34(+) haematopoietic stem/progenitor cells, and not expressed on erythrocytes or platelets. We next examined whether CD48 could serve as a target antigen for mAb therapy against MM. A newly generated in-house anti-CD48 mAb induced mild antibody-dependent cell-mediated cytotoxicity and marked complement-dependent cytotoxicity against not only MM cell lines but also primary MM plasma cells in vitro. Administration of the anti-CD48 mAb significantly inhibited tumour growth in severe combined immunodeficient mice inoculated subcutaneously with MM cells. Furthermore, anti-CD48 mAb treatment inhibited growth of MM cells transplanted directly into murine bone marrow. Finally and importantly, we demonstrated that the anti-CD48 mAb did not damage normal CD34(+) haematopoietic stem/progenitor cells. These results suggest that the anti-CD48 mAb has the potential to become an effective therapeutic mAb against MM.     

Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma (HCC). Both advanced solid tumors and HCV have previously been associated with memory B-cell dysfunction. In this study, we sought to dissect the effect of viral infection, cirrhosis, and liver cancer on memory B-cell frequency and function in the spectrum of HCV disease. Peripheral blood from healthy donors, HCV-infected patients with F1-F2 liver fibrosis, HCV-infected patients with cirrhosis, patients with HCV-related HCC, and non-HCV-infected cirrhotics were assessed for B-cell phenotype by flow cytometry. Isolated B cells were stimulated with anti-cluster of differentiation (CD)40 antibodies and Toll-like receptor (TLR)9 agonist for assessment of costimulation marker expression, cytokine production, immunoglobulin (Ig) production, and CD4(+) T-cell allostimulatory capacity. CD27(+) memory B cells and, more specifically, CD27(+) IgM(+) B cells were markedly less frequent in cirrhotic patients independent of HCV infection. Circulating B cells in cirrhotics were hyporesponsive to CD40/TLR9 activation, as characterized by CD70 up-regulation, tumor necrosis factor beta secretion, IgG production, and T-cell allostimulation. Last, blockade of TLR4 and TLR9 signaling abrogated the activation of healthy donor B cells by cirrhotic plasma, suggesting a role for bacterial translocation in driving B-cell changes in cirrhosis. CONCLUSION: Profound abnormalities in B-cell phenotype and function occur in cirrhosis independent of HCV infection. These B-cell defects may explain, in part, the vaccine hyporesponsiveness and susceptibility to bacterial infection in this population.     

A case of myxoid liposarcoma of the breast

A 70-year-old woman visited a local hospital complaining of a nodulein the right breast, present since 1 month. She was referred to our hospital for further evaluation. Following mammotome (MMT) biopsy, the nodule was diagnosed as myxoid/round cell liposarcoma. She underwent total mastectomy of the right breast. Histological analysis indicated that the tumor was almost entirely composed of proliferating small round mesenchymal cells in amyxoid matrix background with capillary-like vessels with partial necrosis (<10%). Immunohistochemically, p53 positive cells were seen focally (<1%) only, and the Ki-67 labeling index was approximately 20%. Sincethe surgical margin was histologically positive despite pathologic findings of high-grade malignancy, adjuvant treatment involving local radiation therapy (60Gy) was administered. The patient was free from any symptoms of local recurrence and metastases 1 year and 8 months after surgery.     

Early evaluation of transcatheter arterial chemoembolization-refractory hepatocellular carcinoma

Background

There is no standard therapy for patients with transcatheter arterial chemoembolization (TACE)-refractory hepatocellular carcinoma (HCC). This study examined whether evaluating the tumor effect (TE) at 1?week after TACE was useful for predicting refractoriness to TACE.

Methods

We performed a historical cohort study involving 54 patients and 119 tumors. TE was evaluated at 1?week and 3?months after TACE, and an overall evaluation was also performed at 3?months based on the response evaluation criteria in cancer of the liver.

Results

Among 45 tumors evaluated as TE2 at 1?week, 43 tumors (95.6%) were classified as TE1 or TE2 at 3?months. Of the 24 patients whose tumors were categorized as TE2 at 1?week, none achieved a complete or partial response.

Conclusions

Evaluating the TE at 1?week after TACE is useful for the early diagnosis of TACE-refractory HCC and allows alternative treatment options, such as sorafenib, to be employed before the disease progresses.