[Systemic varicella-zoster infection during ixazomib-containing multiagent chemotherapy for multiple myeloma].

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.

A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress.

New drugs have significantly improved the survival of patients with multiple myeloma (MM), but the prognosis of MM patients with high-risk cytogenetic changes such as t(4; 14), t(14; 16) or del17p remains very poor. A natural product, komaroviquinone (KQN), was originally isolated from the perennial semi-shrub Dracocephalum komarovi and has anti-protozoal activity against Trypanosoma cruzi, the organism causing Chagas' disease. Here we demonstrate that a novel KQN-derivative, GTN024, has an anti-MM effect both in vitro and in vivo. GTN024 induced the apoptosis of MM cell lines including those with high-risk cytogenetic changes. GTN024 produced reactive oxygen species (ROS) and increased phosphorylated eIF2α. The ROS production and subsequent endoplasmic reticulum (ER) stress are thought to play a key role in GTN024-induced apoptosis, as the apoptosis was completely abrogated by anti-oxidant treatment. In a mouse xenograft model, an intraperitoneal injection of 20 mg/kg of GTN024 significantly delayed tumor growth. Hematological toxicity and systemic toxicity as indicated by weight loss were not observed. These results suggest that the novel KQN-derivative GTN024 could become a candidate drug for treating high-risk MM.

Parvalbumin-producing striatal interneurons receive excitatory inputs onto proximal dendrites from the motor thalamus in male mice.

In rodents, the dorsolateral striatum regulates voluntary movement by integrating excitatory inputs from the motor-related cerebral cortex and thalamus to produce contingent inhibitory output to other basal ganglia nuclei. Striatal parvalbumin (PV)-producing interneurons receiving this excitatory input then inhibit medium spiny neurons (MSNs) and modify their outputs. To understand basal ganglia function in motor control, it is important to reveal the precise synaptic organization of motor-related cortical and thalamic inputs to striatal PV interneurons. To examine which domains of the PV neurons receive these excitatory inputs, we used male bacterial artificial chromosome transgenic mice expressing somatodendritic membrane-targeted green fluorescent protein in PV neurons. An anterograde tracing study with the adeno-associated virus vector combined with immunodetection of pre- and postsynaptic markers visualized the distribution of the excitatory appositions on PV dendrites. Statistical analysis revealed that the density of thalamostriatal appositions along the dendrites was significantly higher on the proximal than distal dendrites. In contrast, there was no positional preference in the density of appositions from axons of the dorsofrontal cortex. Population observations of thalamostriatal and corticostriatal appositions by immunohistochemistry for pathway-specific vesicular glutamate transporters confirmed that thalamic inputs preferentially, and cortical ones less preferentially, made apposition on proximal dendrites of PV neurons. This axodendritic organization suggests that PV neurons produce fast and reliable inhibition of MSNs in response to thalamic inputs and process excitatory inputs from motor cortices locally and plastically, possibly together with other GABAergic and dopaminergic dendritic inputs, to modulate MSN inhibition.

Convergence of Lemniscal and Local Excitatory Inputs on Large GABAergic Tectothalamic Neurons.

Large GABAergic (LG) neurons form a distinct cell type in the inferior colliculus (IC), identified by the presence of dense VGLUT2-containing axosomatic terminals. Although some of the axosomatic terminals originate from local and commissural IC neurons, it has been unclear whether LG neurons also receive axosomatic inputs from the lower auditory brainstem nuclei, i.e., cochlear nuclei (CN), superior olivary complex (SOC), and nuclei of the lateral lemniscus (NLL). In this study we injected recombinant viral tracers that force infected cells to express GFP in a Golgi-like manner into the lower auditory brainstem nuclei to determine whether these nuclei directly innervate LG cell somata. Labeled axons from CN, SOC, and NLL terminated as excitatory axosomatic endings, identified by colabeling of GFP and VGLUT2, on single LG neurons in the IC. Each excitatory axon made only a few axosomatic contacts on each LG neuron. Inputs to a single LG cell are unlikely to be from a single brainstem nucleus, since lesions of individual nuclei failed to eliminate most VGLUT2-positive terminals on the LG neurons. The estimated number of inputs on a single LG cell body was almost proportional to the surface area of the cell body. Double injections of different viruses into IC and a brainstem nucleus showed that LG neurons received inputs from both. These results demonstrated that both ascending and intrinsic sources converge on the LG somata to control inhibitory tectothalamic projections.

[Copper deficiency anemia morphologically mimicking myelodysplastic syndrome].

A 64-year-old man underwent kidney transplantation for progressive chronic renal failure which had developed 8 years after allogeneic bone marrow transplantation for acute myeloid leukemia. Because of post-operative complications, he had been placed on intravenous hyperalimentation. Three months after the transplantation, anemia rapidly progressed (hemoglobin, 7.9 g/dl). The proportion of reticulocytes was 0.2%, but white blood cell and platelet counts remained within normal ranges. Serum iron, vitamin B12, and folate levels were normal. Bone marrow examination showed the presence of ringed sideroblasts and cytoplasmic vacuoles in a fraction of erythroid cells. Megakaryocytes were adequate in number with normal morphology. Although the findings were consistent with refractory anemia with ringed sideroblasts according to the WHO classification, cytoplasmic vacuolations were also observed in myeloid cells, suggesting copper deficiency. Indeed, serum copper and ceruloplasmin levels were found to be low (33 µg/dl and 11 mg/dl, respectively), and oral copper supplementation at a daily dose of 1 mg was initiated. There was a prompt increase in reticulocytes, and the hemoglobin level was normalized within one month, in response to this regimen. In progressive anemia cases with ringed sideroblasts in the bone marrow, copper deficiency should be considered in the differential diagnosis.

Pancytopenia due to pyrimethamine triggered by transplant-associated microangiopathy after allogeneic bone marrow transplantation.

Toxoplasmosis is one of the life-threatening infections that can occur after hematopoietic stem cell transplantation (HSCT) and also solid organ transplantation. The standard treatment for toxoplasmosis is combination therapy with pyrimethamine and sulfadiazine, both of which inhibit folate metabolism. Therefore, therapy with these agents could result in marrow toxicity including megaloblastic anemia or pancytopenia, which is reversible or preventable with folate supplementation. Transplant-associated microangiopathy (TAM) is another situation where folate is required to compensate for increased erythropoiesis due to hemolysis after allogeneic HSCT. Here, we report a case of severe marrow toxicity manifesting as pancytopenia due to low-dose pyrimethamine, which was triggered by TAM after HSCT.

Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208.

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.

Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality.

OBJECTIVE: Myelodysplastic syndromes (MDS) and aplastic anemia (AA) are the most common anemias that require transfusion therapy in Japan. This retrospective survey investigated relationships between iron overload, chelation practices, and morbidity/mortality in patients with these diseases. METHOD: Medical histories of transfusion-dependent patients were assessed at transfusion onset, chelation onset, and study end. RESULTS: Data were collected from 292 patients with MDS, AA, pure red cell aplasia, myelofibrosis, and other conditions. Patients received a mean of 61.5 red blood cell units during the previous year. Fewer than half (43%) of patients had previously received deferoxamine (DFO) therapy. Only 8.6% received daily/continuous DFO. In all, 75 deaths were reported, with cardiac and liver failure noted in 24.0 and 6.7% of cases. Of these, 97% had ferritin levels >1000 ng/mL. Abnormal cardiac and liver function was observed in 21.9% (14/64) and 84.6% (11/13) of all patients assessed. Effective chelation with DFO resulted in improved serum ferritin, liver enzymes, and fasting blood sugar. CONCLUSIONS: Mortality is higher in heavily iron-overloaded patients, with liver and cardiac dysfunction being the primary cause. Daily/continuous chelation therapy was effective at reducing iron burden and improving organ function. Chelation therapy should be initiated once serum ferritin levels exceed 1000 ng/mL.

Human herpesvirus 6 meningoencephalitis in allogeneic hematopoietic stem cell transplant recipients.

We retrospectively investigated the clinical characteristics of human herpesvirus 6 (HHV-6) meningoencephalitis within 100 days after allogeneic hematopoietic stem cell transplantation (HSCT). Of 1148 patients who received transplants between January 1999 and December 2003, 11 patients (0.96%) with HHV-6 meningoencephalitis were identified. Ten of 11 recipients received hematopoietic stem cells from donors other than HLA-identical siblings. Confusion was the most frequent central nervous system (CNS) symptom, and a skin rash with high-grade fever preceded the CNS symptoms in 9 patients. Magnetic resonance imaging of the brain showed an abnormal increased T2 signal in the hypothalamus of 5 patients. Eight patients were treated with ganciclovir, and an improvement of CNS symptoms was obtained in 3 patients; 3 patients treated with acyclovir showed no improvement. Improvement in the meningoencephalitis seemed less frequent in patients with abnormal findings in the hypothalamus than in those without such findings. Because the symptoms of HHV-6 meningoencephalitis mimicked those of cyclosporine- or tacrolimus-induced encephalopathy, the drugs were withdrawn at the onset of CNS symptoms in 10 patients, resulting in the development of grade IV graft-versus-host disease (GVHD) in 5 patients. Three patients died of HHV-6 meningoencephalitis, and 6 died of other causes, including GVHD. In conclusion, HHV-6 meningoencephalitis is a rare but potentially life-threatening complication in patients who undergo allogeneic HSCT. Careful assessment of the clinical findings and the brain may allow early and precise diagnosis of HHV-6 meningoencephalitis and contribute to improving its prognosis.

Ocular complications in a child with acute graft-versus-host disease following cord blood stem cell transplantation: therapeutic challenges.

We present the first child case of pseudomembranous conjunctivitis accompanied by an extensive corneal ulcer with acute graft-versus-host disease (GVHD) after cord blood stem cell transplantation (CBSCT). The histopathology of the pseudomembrane and the ocular changes following its excision were investigated specifically. One week after the excision of pseudomembrane, the extensive corneal epithelial defects had totally disappeared. Pseudomembrane excision may be an effective method of treatment in corneal epithelial defects observed after GVHD.

Effects of immunosuppressive agents on magnesium metabolism early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The calcineurin inhibitors, cyclosporine A (CSA) and tacrolimus, cause hypomagnesemia by suppressing reabsorption of magnesium (Mg) from renal tubules. To assess whether the effect on Mg metabolism after allogeneic hematopoietic stem cell transplantation (HSCT) differs among calcineurin inhibitors, we prospectively evaluated the Mg metabolism in recipients of allogeneic HSCT who received CSA or tacrolimus METHODS: Patients who underwent allogeneic HSCT were enrolled. CSA and tacrolimus were given by continuous infusion starting from day -1. Serum Mg and the total amount of urinary Mg excretion were measured once before starting of CSA or tacrolimus, and once weekly after HSCT for 4 weeks. Mg was supplemented with magnesium l-aspartate by continuous infusion to maintain the serum Mg level >1.4 mEq/L. RESULTS: Thirty-six patients were evaluated (12 in the CSA group, 24 in the tacrolimus group). The serum Mg level began to decrease in both groups at the first week after HSCT, and the mean serum Mg levels were significantly lower in the tacrolimus group than in the CSA group from the first to the third week. The total amount of urinary Mg excretion and Mg supplementation began to increase in both groups at the second week after HSCT, and the amounts in the tacrolimus group were significantly higher than those in the CSA group. CONCLUSIONS: Although both calcineurin inhibitors increased urinary Mg excretion and caused hypomagnesemia shortly after HSCT, the effect was more significant with tacrolimus than with CSA. This observation may explain the higher incidence of renal impairment and encephalopathy in patients receiving tacrolimus.