Histological features of primary tumors after induction or high-dose chemotherapy in high-risk neuroblastoma

Purpose

In the recent years in Japan, an increasing number of patients with neuroblastoma (NB) are being treated by the “delayed local treatment (DL)” policy, undergoing surgery after the completion of high-dose chemotherapy with hematopoietic stem cell rescue (HDC). We reviewed the histopathological findings of second-look operations, including those of patients treated with DL.

Patients

From 1998 to 2013, 26 patients with high-risk NB underwent radical operation following chemotherapy. Surgery was performed after induction chemotherapy in 17 cases (standard; STD), whereas 9 cases completed induction chemotherapy and HDC before undergoing tumor resection (DL). The amount of necrosis and the degree of differentiation within the post-treatment tumor were assessed.

Results

Eighty-eight percent of the tumors showed necrosis in more than 1/3 of the specimen. Two DL cases showed complete disappearance of viable tumor cells. Amount of necrosis did not affect the prognosis of the patient. Tumors with immature, poorly differentiated phenotypes showed an extremely aggressive thereafter. Though not statistically proven, ¹²³I-MIBG (metaiodobenzylguanidine) uptake may be correlated with the amount of viable cells remaining within the tumor, but not with the degree of differentiation.

Conclusions

Our results support the previous reports advocating that tumors that sustain unfavorable histology after chemotherapy behave aggressively thereafter.     

Evaluation of mandibular range of motion in Brazilian children and its correlation to age, height, weight, and gender

This study aimed to measure the active mandibular range of motion (ROM) (mouth opening: MO; right and left lateral movements: RL and LL; protrusion: P) in Brazilian children of both genders and of various ages, weights, and heights, and to establish correlations among such variables. Study subjects (n = 303) were healthy boys and girls, with ages ranging between 6 and 14 years, who were regular students of a public school in the state of S?o Paulo. Analysis of variance and intra-class correlation coefficients were considered significant for p < 0.05. Weak significant correlations were observed between mandibular ROM and age, height, and weight. No statistically significant differences (p > 0.05) were observed regarding mandibular ROM between gender groups. Mean mandibular ROM values showed significant increases (p < 0.05) in relation to age, height, and weight, except for RL (p > 0.05), in the studied age range. Significantly smaller (p < 0.05) mean mandibular ROM values were observed for the intervals of 6 and 7 years of age, 1.15-1.35 m, and 17.30-26.50 kg, in relation to the other ranges. Nonetheless, no differences were observed among mean mandibular ROM values in the ranges 8 to 12-14 years, 1.36-1.75 m, and 47-85 kg. Thus, it is suggested that weight, height, and age variables be considered when obtaining mandibular ROM values, particularly in children aged 6 to 7 years, measuring 1.15-1.35 m, and weighing between 17.3-46.5 kg.     

Locally administered interferon-γ accelerates lipopolysaccharide-induced osteoclastogenesis independent of immunohistological RANKL upregulation

Ayon Haro ER, Ukai T, Yokoyama M, Kishimoto T, Yoshinaga Y, Hara Y. Locally administered interferon‐γ accelerates lipopolysaccharide‐induced osteoclastogenesis independent of immunohistological RANKL upregulation. J Periodont Res 2011; 46: 361–373. © 2011 John Wiley & Sons A/S Background and Objective: Interferon‐γ (IFN‐γ) potently inhibits RANKL‐induced osteoclastogenesis in vitro. In contrast, previous studies have shown that an increase in IFN‐γ expression is correlated with an increase in lipopolysaccharide (LPS)‐induced bone loss in vivo. However, it is not clear whether local IFN‐γ accelerates osteoclastogenesis or not in vivo. Therefore, the aim of this study was to clarify the role of local IFN‐γ in LPS‐induced osteoclastogenesis. Material and Methods: We induced bone loss in calvaria by injecting LPS. One group of mice received an IFN‐γ injection together with LPS injection, while another group received IFN‐γ 2 d after LPS injection. Bone resorption was observed histologically. Next, we stimulated murine bone marrow macrophages with macrophage‐colony stimulating factor and RANKL in vitro. We added different doses of IFN‐γ and/or LPS at 0 or 48 h time points. Cells were stained with tartrate‐resistant acid phosphatase at 72 h. Results: Local administration of IFN‐γ together with LPS injection did not affect osteoclast formation. However, IFN‐γ injected after LPS injection accelerated osteoclast formation. Also, we confirmed that IFN‐γ added at 0 h inhibited RANKL‐induced osteoclastogenesis in vitro. However, inhibition by IFN‐γ added at 48 h was reduced compared with that by IFN‐γ added at 0 h. Interestingly, IFN‐γ together with a low concentration of LPS accelerated osteoclast formation when both were added at 48 h compared with no addition of IFN‐γ. Conclusion: The results suggest that local IFN‐γ accelerates osteoclastogenesis in certain conditions of LPS‐induced inflammatory bone loss.     

Impact of HIV Infection on Transplant Outcomes after Autologous Peripheral Blood Stem Cell Transplantation: A Retrospective Study of Japanese Registry Data

Autologous stem cell transplantation (ASCT) is a treatment option for HIV-positive patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the prognosis after ASCT in HIV-positive Japanese patients remains unclear. The aim of this study was to evaluate the impact of HIV infection on transplant outcomes after ASCT in Japan. Using the national database of the Japan Society for Hematopoietic Cell Transplantation, we retrospectively evaluated patients with NHL (n?=?3862) and MM (n?=?2670) who underwent their first ASCT between 2001 and 2014. The presence of HIV antibody was used to diagnose HIV infection. Fifty-six patients with NHL (1.4%) and 23 with MM (.8%) were positive for HIV antibody. Among patients with NHL overall survival (OS) was lower in HIV-positive patients than in HIV-negative patients (5-year OS: HIV-positive patients, 44% versus HIV-negative patients, 65%; P?<?.001). In a multivariate analysis HIV infection was significantly associated with an increased risk of overall mortality (hazard ratio, 2.30; P?<?.001). The incidence of relapse was higher in HIV-positive patients (P?=?.036), whereas there was a similar incidence of nonrelapse mortality (P?=?.879). OS in patients with MM was similar between those with/without HIV infection (5-year OS: HIV-positive patients, 61% versus HIV-negative patients, 63%; P?=?.988). HIV infection was associated with a higher risk of overall mortality and relapse after ASCT for NHL in a Japanese population.     

Enhanced <Emphasis Type="Italic">AZIN1</Emphasis> RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer

Background

Adenosine-to-inosine (A-to-I) RNA editing is catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes. Recent evidence suggests that RNA editing of antizyme inhibitor 1 (AZIN1) RNA is emerging as a key epigenetic alteration underlying cancer pathogenesis.

Methods

We evaluated AZIN1 RNA editing levels, and the expression of its regulator, ADAR1, in 280 gastric tissues from 140 patients, using a RNA editing site-specific quantitative polymerase chain reaction assays. We also analyzed the clinical significance of these results as disease biomarkers in gastric cancer (GC) patients.

Results

Both AZIN1 RNA editing levels and ADAR1 expression were significantly elevated in GC tissues compared with matched normal mucosa (P?<?0.0001, 0.0008, respectively); and AZIN1 RNA editing was positively correlated with ADAR1 expression. Elevated expression of ADAR1 significantly correlated with poor overall survival (P?=?0.034), while hyper-edited AZIN1 emerged as an independent prognostic factor for OS and disease-free survival in GC patients [odds ratio (OR):1.98, 95% CI 1.17–3.35, P?=?0.011, OR: 4.55, 95% CI 2.12–9.78, P?=?0.0001, respectively]. Increased AZIN1 RNA editing and ADAR1 over-expression were significantly correlated with key clinicopathological factors, such as advanced T stage, presence of lymph node metastasis, distant metastasis, and higher TNM stages in GC patients. Logistic regression analysis revealed that hyper-editing status of AZIN1 RNA was an independent risk factor for lymph node metastasis in GC patients [hazard ratio (HR):3.03, 95% CI 1.19–7.71, P?=?0.02]. Conclusions: AZIN1 RNA editing levels may be an important prognostic biomarker in GC patients, and may serve as a key clinical decision-making tool for determining preoperative treatment strategies in GC patients.

     

A C?As lyase for degradation of environmental organoarsenical herbicides and animal husbandry growth promoters

Arsenic is the most widespread environmental toxin. Substantial amounts of pentavalent organoarsenicals have been used as herbicides, such as monosodium methylarsonic acid (MSMA), and as growth enhancers for animal husbandry, such as roxarsone (4-hydroxy-3-nitrophenylarsonic acid) [Rox(V)]. These undergo environmental degradation to more toxic inorganic arsenite [As(III)]. We previously demonstrated a two-step pathway of degradation of MSMA to As(III) by microbial communities involving sequential reduction to methylarsonous acid [MAs(III)] by one bacterial species and demethylation from MAs(III) to As(III) by another. In this study, the gene responsible for MAs(III) demethylation was identified from an environmental MAs(III)-demethylating isolate, Bacillus sp. MD1. This gene, termed arsenic inducible gene (arsI), is in an arsenic resistance (ars) operon and encodes a nonheme iron-dependent dioxygenase with C⋅As lyase activity. Heterologous expression of ArsI conferred MAs(III)-demethylating activity and MAs(III) resistance to an arsenic-hypersensitive strain of Escherichia coli, demonstrating that MAs(III) demethylation is a detoxification process. Purified ArsI catalyzes Fe²⁺-dependent MAs(III) demethylation. In addition, ArsI cleaves the C⋅As bond in trivalent roxarsone and other aromatic arsenicals. ArsI homologs are widely distributed in prokaryotes, and we propose that ArsI-catalyzed organoarsenical degradation has a significant impact on the arsenic biogeocycle. To our knowledge, this is the first report of a molecular mechanism for organoarsenic degradation by a C⋅As lyase.The metalloid arsenic is the most common environmental toxic substance, entering the biosphere primarily from geochemical sources, but also through anthropogenic activities (1). Arsenic is a group 1 human carcinogen that ranks first on the Agency for Toxic Substances and Disease Registry Priority List of Hazardous Substances (www.atsdr.cdc.gov/SPL/index.html). Microbial arsenic transformations create a global arsenic biogeocycle (1). These biotransformations include redox cycles between the relatively innocuous pentavalent arsenate and the considerably more toxic and carcinogenic trivalent arsenite (2, 3). In addition, many microbes, both prokaryotic and eukaryotic, have arsM genes for inorganic arsenite [As(III)] S-adenosylmethionine methyltransferases that methylate inorganic As(III) to mono-, di-, and tri-methylated species (4, 5). The genes encoding arsenic transforming enzymes are widely distributed, and these arsenic biotransformations have been proposed to play significant roles in the arsenic biogeocycle and in remodeling the terrain in volcanic areas such as Yellowstone National Park and regions of the world with high amounts of arsenic in soil and water such as West Bengal and Bangladesh (3, 6).Arsenicals, both inorganic and organic, have been used in agriculture in the United States for more than a century (7). Historically, the use of inorganic arsenical pesticides/herbicides has been largely replaced by methylated arsenicals such as monosodium methylarsonic acid (MSMA), which is still in use as an herbicide for turf maintenance on golf courses, sod farms, and highway rights of way, and for weed control on cotton fields (7). More complex pentavalent aromatic arsenicals such as roxarsone [4-hydroxy-3-nitrophenylarsonic acid, Rox(V)] have been largely used since the middle of the 1940s as antimicrobial growth promoters for poultry and swine to control Coccidioides infections and improve weight gain, feed efficiency, and meat pigmentation (8, 9). These aromatic arsenicals are largely excreted unchanged and introduced into the environment when chicken litter is applied to farmland as fertilizer (8). Pentavalent organoarsenicals are relatively benign and less toxic than inorganic arsenicals; however, aromatic (8–10) and methyl (11, 12) arsenicals are degraded into more toxic inorganic forms in the environment, which may contaminate the foods and water supplies. Although microbial degradation of environmental organoarsenicals has been documented (8, 9, 11, 13), no molecular details of the reaction have been reported. We recently demonstrated that a microbial community in Florida golf course soil carries out a two-step pathway of MSMA reduction and demethylation (14). Here we report the isolation of an environmental methylarsonous acid [MAs(III)]-demethylating bacterium Bacillus sp. MD1 (for “MAs(III) demethylating”) from Florida golf course soil and the cloning of the gene, termed arsenic inducible gene (arsI), responsible for MAs(III) demethylation. The gene product, ArsI, is nonheme iron-dependent dioxygenase with C⋅As lyase activity. ArsI cleaves the C⋅As bond in a wide range of trivalent organoarsenicals, including the trivalent roxarsone [Rox(III)], into As(III), which strongly suggests that the environmental pentavalent phenylarsenicals such as Rox(V) also undergo a two-step pathway of sequential reduction and ArsI-catalyzed dearylation, in analogy with the demethylation of MSMA by a microbial community. Thus, ArsI-catalyzed C⋅As bond cleavage is a newly identified mechanism for degradation of organoarsenical herbicides and antimicrobial growth promoters.     

Comparison of the effects of pre-dilution and post-dilution online hemodiafiltration on the levels of inflammatory markers,lymphocytes, and platelets

Journal of Artificial Organs - Online hemodiafiltration (OL-HDF) is a blood purification therapy based on diffusion and ultrafiltration and is classified into two types according to the mode of...