Elevated level of serum cystatin-C concentration is a useful predictor for myelosuppression induced by methotrexate for treatment of rheumatoid arthritis

Methotrexate (MTX) is indispensable for the treatment of rheumatoid arthritis (RA). However, a small number of patients treated with MTX occasionally encounter some life-threatening events, including myelosuppression. Renal insufficiency, one of risk factors for these events, is difficult to assess because the serum creatinine concentration level and estimated glomerular filtration rate are sometimes inaccurately determined in aged RA patients. As a better indicator to evaluate this pathology, we measured the serum cystatin-C (Cys-C) level in 78 RA patients ≥50 years who were treated with MTX and observed for a year. The measurement achieved successful screening of two patients with leukocytopenia, one with interstitial lung disease (ILD), and two with liver dysfunction. An additional four referral inpatients with MTX-induced adverse events (three with pancytopenia, one with ILD) were enrolled for analysis, amounting to 82 patients. The logistic regression analysis showed that a correlation was observed between myelotoxicity and serum Cys-C level (elevation per 0.1 mg/dl; odds ratio 2.34, 95% confidence interval 1.08–5.09, p = 0.03). In conclusion, elderly RA patients potentially have subclinical renal insufficiency detected by the serum Cys-C concentration level. The elevated level of serum Cys-C is a more sensitive indicator to predict MTX-induced myelotoxicity than that of serum creatinine.     

Successful treatment of refractory enteropathy-associated T-cell lymphoma using high-dose chemotherapy and autologous stem cell transplantation

A 65-year-old woman presented with a 6-month history of abdominal pain and watery diarrhea. Type II enteropathy-associated T-cell lymphoma (EATL) was diagnosed based on the clinical presentation and pathological examination of the tumor. The patient received combination chemotherapy but did not achieve remission. Subsequently, high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) were performed. After these therapies, she achieved complete remission, which has been sustained for 18 months. Although the role of HDT-ASCT for EATL is still controversial, the clinical course of this patient suggests that ASCT can improve the prognosis in some patients with EATL.     

Risk factors for massive blood loss during liver resection for hepatocellular carcinoma in patients with cirrhosis

BACKGROUND/AIMS: Liver resection for hepatocellular carcinoma in patients with cirrhosis carries risk of major hemorrhage and sometimes requires blood transfusion. We investigated risk factors for massive blood loss during liver resection and indications for storing blood for autologous intraoperative transfusion. METHODOLOGY: We analyzed clinical records of 100 patients with cirrhosis who underwent liver resection for hepatocellular carcinoma. Autologous blood was stored preoperatively for 19 patients. RESULTS: Intraoperative blood loss ranged from 5 to 3000 mL (mean, 640). Liver resection was performed without transfusion in 67 patients and with autologous blood storage in 17 patients not receiving homologous blood. In the other 16 patients, homologous blood was transfused. Univariate analysis identified youth, large tumors (> 4cm), major hepatectomy, portal tumor involvement, hepatic vein involvement, and prolonged operation time as risk factors for massive blood loss; multivariate analysis identified portal involvement and hepatic vein involvement as independent risk factors. Blood loss exceeded 1000 mL in the 4 transfused group B patients and 3 of the 4 patients had hepatic vein involvement. CONCLUSIONS: Portal involvement and hepatic vein involvement were risk factors for massive blood loss during liver resection for hepatocellular carcinoma in patients with cirrhosis. Autologous blood storage is indicated in patients with such risk factors.     

In situ cross-linkable hyaluronan hydrogels containing polymeric nanoparticles for preventing postsurgical adhesions

OBJECTIVE: To develop a combined barrier method and drug delivery system ("hybrid system") for preventing postoperative peritoneal adhesions, which could combine the biocompatibility and ease of application of in situ cross-linkable hydrogels with the controlled release features of polymeric nanoparticles. METHODS: Poly(lactic-co-glycolic acid) nanoparticles were dispersed in aldehyde- and hydrazide-modified hyaluronic acids (HA), then combined via a double-barreled syringe. The material was subjected to mechanical testing and was assayed for in vitro cytotoxicity to murine mesothelial cells. Subsequently, it was tested for biocompatibility by intraperitoneal injection in mice. The hybrid's effectiveness in preventing postsurgical adhesions was assessed using a rabbit sidewall defect-cecum abrasion model, where it was applied to both injured surfaces. RESULTS: The in situ hybrid gel system formed a flexible and durable hydrogel in less than 10 seconds. It had low in vitro cytotoxicity. In the mouse, the cross-linked HA maintained the polymeric nanoparticles in the peritoneum for 1 week, which we had previously shown would have cleared in less than 2 days, and no animals developed adhesions. Notably, the hybrid gel, even in the absence of encapsulated drug, was highly effective in preventing peritoneal adhesions in the rabbit model employed. Animals treated with the hybrid (n = 8) had no adhesions in 62.5% of cases, and none had adhesions that could only be separated by sharp dissection. In contrast, only 4.2% of untreated animals (n = 24) had no adhesions, and 58.3% developed adhesions requiring sharp dissection. CONCLUSIONS: The hybrid cross-linked HA-nanoparticle system described here appears to be a biocompatible and highly effective adhesion barrier, which could also deliver antiadhesion drugs.     

Inhibition of ATP-sensitive K+ channels and L-type Ca2+ channels by amiodarone elicits contradictory effect on insulin secretion in MIN6 cells

Some class I antiarrhythmic drugs induce a sporadic hypoglycemia by producing insulin secretion via inhibition of ATP-sensitive K(+) (K(ATP)) channels of pancreatic β-cells. It remains undetermined whether amiodarone produces insulin secretion by inhibiting K(ATP) channels. In this study, effects of amiodarone on K(ATP) channels, L-type Ca(2+) channel, membrane potential, and insulin secretion were examined and compared with those of quinidine in a β-cell line (MIN6). Amiodarone as well as quinidine inhibited the openings of the K(ATP) channel in a concentration-dependent manner without affecting its unitary amplitude in inside-out membrane patches of single MIN6 cells, and the IC(50) values were 0.24 and 4.9 μM, respectively. The L-type Ca(2+) current was also inhibited by amiodarone as well as quinidine in a concentration-dependent manner. Although glibenclamide (0.1 μM) or quinidine (10 μM) significantly potentiated the insulin secretion from MIN6 cells, amiodarone (1-30 μM) failed to increase insulin secretion. Amiodarone (30 μM) and nifedipine (10 μM) significantly inhibited the increase in insulin secretion produced by 0.1 μM glibenclamide. Amiodarone (30 μM) produced a gradual decrease of the membrane potential, but did not produce repetitive electrical activity in MIN6 cells. Glibenclamide (1 μM) produced a slow depolarization, followed by spiking activity which was inhibited by 30 μM amiodarone. Thus, amiodarone is unlikely to produce hypoglycemia in spite of potent inhibitory action on K(ATP) channels in insulin-secreting cells, possibly due to its Ca(2+) channel-blocking action.     

A case of atypical teratoid/rhabdoid tumor in an adult, with long survival

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that mostly occurs in early childhood and has poor prognosis despite aggressive therapy. Adult cases are rare and, as far as we are aware, only 30 cases have been reported to date. Here we present the case of a 27-year-old female with left parietal AT/RT with the chief complaint of numbness of the right superior limb. First, the tumor was surgically removed and the diagnosis was grade II glioma. With additional radiotherapy, the clinical course after surgery was favorable. After 6 years, she had an operation for recurrence and the diagnosis was grade III glioma. Temozolomide was prescribed, and a disease-free period of 2 years followed. Surgery was performed for a third time for second recurrence with histology of diffuse growth of rhabdoid cells. Immunohistochemistry was partially positive for vimentin and epithelial membrane antigen. Ki-67 labeling index was extremely high and tumor cells showed no staining of INI1 suggestive of diagnosis of AT/RT. We re-evaluated past specimens and none had immunoreactivity of INI1. Ki-67 labeling index and O-6 methylguanine DNA methyltransferase (MGMT) staining were also re-examined and both increased gradually. She is still alive without recurrence for more than 1 year. As far as we are aware, this is the second longest survival of an adult with AT/RT.     

Usage of granulocyte colony-stimulating factor every 2 days is clinically useful and cost-effective for febrile neutropenia during early courses of chemotherapy

Background  

In order to analyze the clinical activity and cost-effectiveness of granulocyte colony-stimulating factors (G-CSF), the prophylactic usage of G-CSF in patients treated with a single chemotherapy regimen during early courses was prospectively evaluated.     

Survival of skin allografts is prolonged in mice with a dominant-negative H-Ras

Ras is a guanine nucleotide-binding protein that plays a major role in regulating the proliferation of T cells. To investigate the mechanism of the Ras/mitogen-activated protein kinase pathway, one of the downstream signal-transduction pathways of T-cell receptors, in the response to alloantigen, we performed full-thickness skin grafting in the major histocompatibility complex (MHC) incompatible strain BALB/c (H-2Kd) (donor) and T-cell-specific H-Ras dominant-negative (dnRas) transgenic (tg) C57BL/6 (H-2Kb) (recipient) male mice. In vitro and in vivo dnRas tg mouse T-cell proliferation and cytotoxic T lymphocyte (CTL) activity assay were also performed. The median graft survival time in control B6/wild type (wt) mouse allografts was seven days. Conversely, the dnRas tg mouse group exhibited a significant (p<0.01) prolongation of graft survival to 15 days. However, all grafts were eventually rejected after one month. Mixed lymphocyte reaction and popliteal lymph node assay revealed that T-cell proliferation was decreased in response to alloantigen, but CTL activity was not changed in the dnRas tg mice. These results suggested that Ras is essential for peripheral T lymphocytes to respond to allo-MHC antigens, and Ras may be a molecular target for controlling transplant rejection.