Post-transplant consolidation therapy using thalidomide alone for the patients with multiple myeloma: a feasibility study in Japanese population

In order to test for improved survival following autologous transplantation (ASCT), we conducted a prospective clinical trial of post-ASCT thalidomide therapy in Japanese patients with multiple myeloma (MM). Twenty-five newly diagnosed patients received double or single ASCT with high-dose melphalan (200?mg/m²). Two months after stem cell infusion, if the patients failed to achieve a near-complete response, thalidomide was administered at 200?mg/day until disease progression or occurrence of intolerable adverse events. Seventeen patients were in partial response or minimal response after ASCT and received thalidomide alone. Their median progression-free survival (PFS) from ASCT was 17.4?months, and the median overall survival (OS) was 42.9?months. Some patients with normal karyotype experienced durable disease stabilization for over 5?years. Five patients who exhibited high-risk chromosomal changes such as t(4;14) or deletion of chromosome 13 or 17 showed very short PFS and OS compared with those who did not. Observed grade 3 or 4 toxicities included infection in three patients, hematological toxicities in three, and gastrointestinal toxicities in two, but there was no grade 3 or higher peripheral neuropathy, probably due to appropriate dose modifications. This long-term prospective study is the first to demonstrate the feasibility of post-ASCT thalidomide therapy in Japanese patients with MM.     

A case of catastrophic antiphospholipid antibody syndrome complicated with systemic lupus erythematosus, double positive for anti-cardiolipin/β2 glycoprotein?I and anti-phosphatidylserine/prothrombin autoantibodies

A 16-year-old male with severe thrombocytopenia and progressive multiple organ infarctions was diagnosed as having catastrophic antiphospholipid syndrome (CAPS) complicated with systemic lupus erythematosus, and was successfully treated with combination of anticoagulants, corticosteroids, plasma exchange, and intravenous cyclophosphamide. Antibodies to phosphatidylserine/prothrombin (PS/PT) complex and cardiolipin (CL)/β(2)-glycoprotein?I (β(2)GPI) were simultaneously detected, indicating that the different pathways of both PS/PT and CL/β(2)GPI might be associated with the radical manifestation of CAPS.     

Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease

Background

Klotho is a single-pass transmembrane protein, which appears to be implicated in aging. The purpose of the present study was to characterize the relationship between the soluble Klotho level and renal function in patients with various degrees of chronic kidney disease (CKD).

Methods

The levels of soluble Klotho in the serum and urine obtained from one hundred thirty-one CKD patients were determined by a sandwich enzyme-linked immunosorbent assay system.

Results

The amount of urinary excreted Klotho during the 24 hr period ranged from 1.6 to 5178 ng/day (median 427 ng/day; interquartile range [IR] 56.8-1293.1), and the serum Klotho concentration ranged from 163.9 to 2123.7 pg/ml (median 759.7 pg/ml; IR 579.5-1069.1). The estimated glomerular filtration rate (eGFR) was significantly correlated with the log-transformed values of the amount of 24 hr urinary excreted Klotho (r?=?0.407, p?<?0.01) and the serum Klotho levels (r?=?0.232, p?<?0.01). However, a stepwise multiple regression analysis identified eGFR to be a variable independently associated only with the log-transformed value of the amount of 24-hr urinary excreted Klotho but not with the log-transformed serum Klotho concentration. Despite the strong correlation between random urine protein-to-creatinine ratio and the 24 hr urinary protein excretion (r?=?0.834, p?<?0.01), a moderate linear association was observed between the log-transformed value of the amount of 24 hr urinary excreted Klotho and that of the urinary Klotho-to-creatinine ratio (Klotho/Cr) in random urine specimens (r?=?0.726, p?<?0.01).

Conclusions

The amount of urinary Klotho, rather than the serum Klotho levels, should be linked to the magnitude of the functioning nephrons in CKD patients. The use of random urine Klotho/Cr as a surrogate for the amount of 24-hr urinary excreted Klotho needs to be evaluated more carefully.

     

The efficacy and safety of mizoribine for maintenance therapy in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis: the usefulness of serum mizoribine monitoring

Clinical and Experimental Nephrology - The life prognosis of elderly patients with myeloperoxidase–anti-neutrophil cytoplasmic antibodies-associated vasculitis (MPO-AAV) has been improved by...     

Pharmacodynamic Actions of a Long‐Acting PTH Analog (LA‐PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys

Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long‐acting PTH analog, [Ala^1,3,12,18,22, Gln¹⁰,Arg¹¹,Trp¹⁴,Lys²⁶]‐PTH(1‐14)/PTHrP(15‐36) (LA–PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intravenous administration of LA‐PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near‐normal levels for longer than 48 hours, whereas PTH(1‐34) and PTH(1‐84), each injected at a dose 80‐fold higher than that used for LA‐PTH, increased sCa and decreased sPi only modestly and transiently (<6 hours). LA‐PTH also exhibited enhanced and prolonged efficacy versus PTH(1‐34) and PTH(1‐84) for elevating sCa when administered subcutaneously (s.c.) into monkeys. Daily s.c. administration of LA‐PTH (1.8 nmol/kg) into TPTX rats for 28 days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long‐acting PTH analogs as potential therapies for patients with hypoparathyroidism. © 2016 American Society for Bone and Mineral Research.     

A case of myeloid sarcoma diagnosed by FISH

Myeloid sarcoma (MS) is a tumor mass of myeloblasts or immature myeloid cells occurring in an extramedullary site or in bone. The tumor mass may precede or occur concurrently with acute or chronic myeloid leukemia or with other types of myeloproliferative disorders or myelodysplastic syndromes. MS is a rare disease, estimated to comprise between 2 to approximately 14% of acute myeloid leukemia. On the other hand, 95% of cases of CML have characteristic t (9;22) cytogenetic abnormality and BCR/ABL fusion gene at diagnosis. We here report the clinical significance of FISH in a diagnosis of MS that formed tumor in femur during the chronic phase of CML.     

Distinct intraspecific variations of garlic (Allium sativum L.) revealed by the exon–intron sequences of the alliinase gene

Garlic (Allium sativum L.) has been used worldwide as a food and for medicinal purposes since early times. Garlic cultivars exhibit considerable morphological diversity despite the fact that they are mostly sterile and are grown only by vegetative propagation of cloves. Considerable recombination occurs in garlic genomes, including the genes involved in secondary metabolites. We examined the genomic DNAs (gDNAs) from garlic, encoding alliinase, a key enzyme involved in organosulfur metabolism in Allium plants. The 1.7-kb gDNA fragments, covering three exons (2, 3, and 4) and all four introns, were amplified from total DNAs prepared from garlic samples produced in Asia and Europe, leading to 73 sequences in total: Japan (JPN), China (CHN), India (IND), Spain (ESP), and France (FRA). The exon sequences were highly conserved among all the sequences, probably reflecting the fully functional alliinase associated with the flavor quality. Distinct intraspecific variations were detected for all four intron sequences, leading to the haplotype classifications. A close relationship between JPN and CHN was observed for all four introns, whereas IND showed a more divergent distribution. ESP and FRA afforded clearly different variants compared with those from Asian sequences. The present study provides information that could be useful in the development of an additional molecular marker for garlic authentication and quality control.     

Promotion of normal healing of bone defects under estrogen deficiency by implantation of beta‐tricalcium phosphate composed of rod‐shaped particles

We compared the healing of bone defects in ovariectomized rats implanted with beta‐tricalcium phosphate (β‐TCP) composed of rod‐shaped particles, which were prepared using the applied hydrothermal method (HTCP), and that of bone defects implanted with conventional β‐TCP composed of globular‐shaped particles (CTCP), which were prepared by normal sintering. Eight‐week‐old female Wistar rats were ovariectomized, and 2 weeks after the operation, 0.5‐ to 0.6‐mm diameter spherical granules of each ceramic were implanted in a bone defect created in the distal end of the femur. Four, 8, and 12 weeks after implantation, the amount of newly formed bone implanted with HTCP was significantly larger than that implanted with CTCP and was equivalent to that in non‐ovariectomized sham‐operated rats. Without implantation, spontaneous repair of the trabecular bone was barely observed. The physiological structure of the trabecular network was maintained in the region implanted with HTCP, but that in the region implanted with CTCP was severely destroyed. Gene expression microarray analysis revealed that the expression of genes involved in interferon signaling pathways was upregulated in osteoclasts cultured on HTCP compared with that cultured on CTCP. Our results suggest that the microstructure of β‐TCP affected the biological behavior of osteoclasts and regulated local bone metabolism. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:189–196, 2014.     

New-onset psychiatric disorders after corticosteroid therapy in systemic lupus erythematosus: an observational case-series study

The objective of this study was to clarify the incidence, clinical characteristics, and courses of new-onset psychiatric manifestations after corticosteroid therapy in patients with systemic lupus erythematosus (SLE), including possible ways of differentiating between corticosteroid-induced psychiatric disorders (CIPDs) and central nervous system manifestations of SLE (CNS-SLE). We prospectively followed for 8 weeks 139 consecutive episodes in 135 in-patients who had a non–CNS-SLE flare treated with corticosteroids. Psychiatric events were evaluated once a week using DSM-IV criteria. We then conducted a post hoc etiological analysis of any newly developed psychiatric events during this follow-up period. In the 8 weeks of corticosteroid administration, new psychiatric events occurred in 20 (14.4 %) of the 139 episodes. The mean dosage of corticosteroids administered was prednisolone at 0.98 (range 0.24–1.39) mg/kg/day. Of the 20 psychiatric events, 14 (10.1 %) were suitable for the strict definition of CIPDs, accompanied by mood disorders in 13 (depressive in 2, manic in 9, and mixed in 2) and psychotic disorder in one. Two (1.4 %), both presenting delirium, were diagnosed as CNS-SLE on the basis of evidence of abnormal CNS findings even before psychiatric manifestations, all of which improved in parallel with these patients’ recoveries through augmentation of immunosuppressive therapy. The other four events (2.9 %) could not be etiologically identified. This study suggests that corticosteroid therapy triggers CIPDs and CNS-SLE in patients with SLE. Delirium may be suggestive of CNS-SLE, while mood disorders may be more suggestive of CIPDs. Electroencephalographic abnormalities may possibly be predictive of CNS-SLE.