Peripheral Neuropathy and VIth Nerve Palsy Related to Randall Disease Successfully Treated by High-Dose Melphalan, Autologous Blood Stem Cell Transplantation, and VIth Nerve Decompression Surgery

Randall disease is an unusual cause of extraocular motor nerve (VI) palsy. A 35-year-old woman was hospitalized for sicca syndrome. The physical examination showed general weakness, weight loss, diplopia related to a left VIth nerve palsy, hypertrophy of the submandibular salivary glands, and peripheral neuropathy. The biological screening revealed renal insufficiency, serum monoclonal kappa light chain immunoglobulin, urinary monoclonal kappa light chain immunoglobulin, albuminuria, and Bence-Jones proteinuria. Bone marrow biopsy revealed medullar plasma cell infiltration. Immunofixation associated with electron microscopy analysis of the salivary glands showed deposits of kappa light chains. Randall disease was diagnosed. The patient received high-dose melphalan followed by autostem cell transplantation which led to rapid remission. Indeed, at the 2-month followup assessment, the submandibular salivary gland hypertrophy and renal insufficiency had disappeared, and the peripheral neuropathy, proteinuria, and serum monoclonal light chain had decreased significantly. The persistent diplopia was treated with nerve decompression surgery of the left extraocular motor nerve. Cranial nerve complications of Randall disease deserve to be recognized.

Role of Free Light Chain Assay Ratio to Distinguish Between CR According EBMT Criteria or Stringent Complete Remission (sCR) According IMWG in Multiple Myeloma Patients.

Abstract 1787 Poster Board I-813 Introduction The qualitative assay for free light chain has been reported to be sensitive and specific for detecting and monitoring diseases caused by monoclonal gammopathies such as multiple myeloma. More recently the International Myeloma Working Group proposed uniform response criteria including a new definition of stringent complete remission (sCR). The definition of stringent complete remission requires beside absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence also normalization of free light chain ratio in serum. Patients and Methods We evaluate the value of free light chain assay to determine stringent CR by monitoring 87 patients with multiple myeloma who achieved complete remission (n=52) or very good partial remission (n=35) between January 2003 and December 2008. Free light chain measurements were performed with the commercially available Free liteTM Kit (Binding Site, Heidelberg, Germany). Because of the shorter half-life of free light chain assay ratio, only patients were included, if the complete or very good partial remission remains stable for at least 3 months. The comparison between immunofixation and free light chain ratio was performed at least 6 weeks after immunofixation becomes negative for the first time. 87 patients (50 mal and 37 female) were included, 67 had intact immunoglobulin and 11 had light chain immunoglobulin at time of diagnosis. The remission status was determined either after allogeneic (n = 73) or autologous (n = 7) stem cell transplantation or after conventional bortezomib or lenalidomide containing chemotherapy (n = 7). Results 35 out of 87 patients achieved a very good partial or near complete remission with still positive immunofixation. In 22 out of those 35 patients the free light chain kappa ratio was within the normal range of 0.26 – 1.65 mg/l (63 %). Only in 13 patients with persistent immunofixation positivity the free light chain ratio was outside the normal range (37%). 52 patients achieved complete remission according to the EBMT criteria with negative immunofixation for at least 3 months. In those patients all (100 %) had a normal free light chain kappa/lambda ratio. In a subgroup of patients (n = 10) who relapsed during follow-up from complete remission sequential monitoring of immunofixation and free light assay was performed as recently described [4]. In 9 out of 10 patients a free light chain ratio became abnormal at a median 90 days before immunofixation became positive. Conclusions The free light chain assay ratio is a useful marker for a faster detection of remission or progression in myeloma patients. However, these results do not support additional value of free light chain ratio to determine the depth of remission in immunofixation negative patients. More sensitive methods such as imunophenotyping analysis by FACS or molecular primer should be used to determine depth of complete remission since these methods have shown relevant clinical impact. Disclosures No relevant conflicts of interest to declare.

Dysregulation of Frizzled 6 is a critical component of B-cell leukemogenesis in a mouse model of chronic lymphocytic leukemia

Wnt/Fzd signaling is known to play a key role in development, tissue-specific stem-cell maintenance, and tumorigenesis, particularly through the canonical pathway involving stabilization of β-catenin. We have previously shown that Fzd9−/− mice have a deficiency in pre-B cells at a stage when self-renewing division is occurring in preference to further differentiation, before light chain immunoglobulin recombination. To determine whether pathologic usurpation of this pathway plays a role in B-cell leukemogenesis, we examined the expression of Wnt/Fzd pathway genes in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia. We find that, in the course of leukemogenesis, the expression of Wnt16, Wnt10α, Fzd1, and most dramatically, Fzd6, is progressively up-regulated in the transformed CD5+ B cells of these mice, as are β-catenin protein levels. Elimination of Fzd6 expression by crossing into Fzd6−/− mice significantly delays development of chronic lymphocytic leukemia in this model. Our findings suggest that the self-renewal signals mediated by Wnt/Fzd that are enlisted during B-cell development may be pathologically reactivated in the neoplastic transformation of mature B cells.