Antitumor activity of pan‐HER inhibitors in HER2‐positive gastric cancer

Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti‐human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti‐HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2‐positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan‐HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2‐amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin‐like growth factor‐1 receptor (IGF‐1R), were less sensitive to pan‐HER inhibitors. A combination therapy consisting of pan‐HER inhibitors and an IGF‐1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2‐amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF‐1R‐targeting therapy can overcome drug insensitiveness in HER2‐amplified gastric cancer.     

Carcinogenicity studies of 1,4-dioxane administered in drinking-water to rats and mice for 2 years

The carcinogenicity of 1,4-dioxane was examined by giving groups of 50 F344/DuCrj rats and 50 Crj:BDF₁ mice of each sex 1,4-dioxane in the drinking-water for 2 years. The concentrations of 1,4-dioxane were 0 (control), 200, 1000 and 5000 ppm (wt./wt.) for rats and 0, 500, 2000 and 8000 ppm for mice. The highest dose levels did not exceed the maximum tolerated dose. In the rat, there was significant induction of nasal squamous cell carcinomas in females and hepatocellular adenomas and carcinomas in males and females, peritoneal mesotheliomas in males, and mammary gland adenomas in females. In the mouse, there was significant induction of hepatocellular tumors in males and females. Two nasal tumors occurring in the 8000 ppm-dosed groups were spontaneously rare and, thus, were attributed to 1,4-dioxane exposure. The present studies provided clear evidence of carcinogenicity in rats and mice. Lifetime cancer risk of humans exposed to 1,4-dioxane through drinking-water was quantitatively estimated with a non-threshold approach by application of a linearized multistage model to dose–carcinogenic response relationships, in addition to a threshold approach for estimation of the tolerable daily intake using no-observed- or lowest-observed-adverse-effect levels of the carcinogenic responses and uncertainty factors.     

The herbal medicine Shosaiko-to exerts different modulating effects on lung local immune responses among mouse strains.

Shosaiko-to (SST), a Chinese/Japanese traditional herbal medicine, has recently been demonstrated to increase lung interleukin-6 (IL-6) levels and to ameliorate pulmonary disorders in BALB/c mice (BALB). In the present study, we examined the effects of SST on lung cytokine levels and lipopolysaccharide (LPS)-induced lung injury in C57BL/6 mice (B6), which are known to show different immune responses from BALB due to the difference in genetic backgrounds. In B6, in contrast with BALB, SST decreased lung IL-6 levels and exacerbated LPS-induced lung injury. Investigation of the active components of SST suggested that multiple ingredients were supposed to be responsible for IL-6-attenuating activity in vivo. Further, we examined the effect of metabolites of major ingredients of SST on IL-6 production from lung immune cells in vitro. Saikogenin D and oroxylin A attenuated IL-6 production in LPS-stimulated alveolar macrophages of B6 more than in that of BALB. Liquiritigenin, which was previously reported to enhance IL-6 production in anti-CD3 monoclonal antibody-stimulated lung mononuclear cells of BALB, showed no effect on that of B6. These findings suggest that SST may have different, possibly even opposite, effects on lung immunity in hosts with different genetic backgrounds.     

Speciation of arsenic in biological samples

Speciation of arsenicals in biological samples is an essential tool to gain insight into its distribution in tissues and its species-specific toxicity to target organs. Biological samples (urine, hair, fingernail) examined in the present study were collected from 41 people of West Bengal, India, who were drinking arsenic (As)-contaminated water, whereas 25 blood and urine samples were collected from a population who stopped drinking As contaminated water 2 years before the blood collection. Speciation of arsenicals in urine, water-methanol extract of freeze-dried red blood cells (RBCs), trichloroacetic acid treated plasma, and water extract of hair and fingernail was carried out by high-performance liquid chromatography (HPLC)-inductively coupled argon plasma mass spectrometry (ICP MS). Urine contained arsenobetaine (AsB, 1.0%), arsenite (iAs(III), 11.3), arsenate (iAs(V), 10.1), monomethylarsonous acid (MMA(III), 6.6), monomethylarsonic acid (MMA(V), 10.5), dimethylarsinous acid (DMA(III), 13.0), and dimethylarsinic acid (DMA(V), 47.5); fingernail contained iAs(III) (62.4%), iAs(V) (20.2), MMA(V) (5.7), DMA(III) (8.9), and DMA(V) (2.8); hair contained iAs(III) (58.9%), iAs(V) (34.8), MMA(V) (2.9), and DMA(V) (3.4); RBCs contained AsB (22.5%) and DMA(V) (77.5); and blood plasma contained AsB (16.7%), iAs(III) (21.1), MMA(V) (27.1), and DMA(V) (35.1). MMA(III), DMA(III), and iAs(V) were not found in any plasma and RBCs samples, but urine contained all of them. Arsenic in urine, fingernails, and hair are positively correlated with water As, suggesting that any of these measurements could be considered as a biomarker to As exposure. Status of urine and exogenous contamination of hair urgently need speciation of As in these samples, but speciation of As in nail is related to its total As (tAs) concentration. Therefore, total As concentrations of nails could be considered as biomarker to As exposure in the endemic areas.     

Medium-term oncological and functional outcomes of hemi-gland brachytherapy using iodine-125 seeds for intermediate-risk unilateral prostate cancer

PURPOSETo examine medium-term outcomes of hemi-gland low-dose-rate brachytherapy as a primary treatment for intermediate-risk prostate cancer.METHODSWe recruited intermediate-risk unilateral prostate cancer patients for a prospective trial of hemi-gland brachytherapy. Twenty-four patients underwent hemi-gland iodine-125 seed implantation with a prescribed dose of 160 Gy. Serum prostate-specific antigen (PSA) was measured regularly and follow-up biopsy was scheduled after 2–3 years of treatment. When clinically needed afterward, for-cause biopsy was performed to confirm pathology. Treatment failure (TF)-free survival, which was defined as freedom from radical or systemic therapy, metastases, and cancer-specific mortality, was assessed, as was biochemical failure (BF)-free survival. Urinary and sexual functions were also evaluated.RESULTSMedian follow-up duration was 61 months. Twenty-two patients (92%) exhibited a declining trend or decreased value of PSA for 12 months or longer after the treatment. Follow-up biopsy in the initial triennium and for-cause biopsy in the subsequent triennium were performed in 16 and four patients, respectively, and cancer was found from the treated lobe in one patient (4% of the cohort) and significant cancer was found from untreated lobes in four patients (17%) in total. Secondary treatments were performed in six patients successfully. Five-year freedom from BF, TF, and metastasis was 71%, 90%, and 100%, respectively. The International Prostate Symptom Score significantly deteriorated at 3 months and reversed itself afterward. The International Index of Erectile Function 5 had no significant decrease.CONCLUSIONSHemi-gland low-dose-rate brachytherapy provides favorable medium-term oncological outcomes with genito-urinary functional preservation for men with intermediate-risk unilateral prostate cancer.     

Inhalation of concentrated ambient air particles exacerbates myocardial ischemia in conscious dogs

Short-term increases in ambient air pollution have been associated with an increased incidence of acute cardiac events. We assessed the effect of inhalation exposure to concentrated ambient particles (CAPs) on myocardial ischemia in a canine model of coronary artery occlusion. Six mongrel dogs underwent thoracotomy for implantation of a vascular occluder around the left anterior descending coronary artery and tracheostomy to facilitate particulate exposure. After recovery (5-13 weeks), pairs of subjects were exposed for 6 hr/day on 3 or 4 consecutive days. Within each pair, one subject was randomly assigned to breathe CAPs on the second exposure day and filtered air at other times. The second subject breathed CAPs on the third exposure day and filtered air at other times. Immediately after each exposure, subjects underwent 5-min coronary artery occlusion. We determined ST-segment elevation, a measure of myocardial ischemia heart rate, and arrhythmia incidence during occlusion from continuous electrocardiograms. Exposure to CAPs (median, 285.7; range, 161.3-957.3 microg/m3) significantly (p = 0.007) enhanced occlusion-induced peak ST-segment elevation in precordial leads V4 (9.4 +/- 1.7 vs. 6.2 +/- 0.9 mm, CAPs vs. filtered air, respectively) and V5 (9.2 +/- 1.3 vs. 7.5 +/- 0.9 mm). ST-segment elevation was significantly correlated with the silicon concentration of the particles and other crustal elements possibly associated with urban street dust (p = 0.003 for Si). No associations were found with CAPs mass or number concentrations. Heart rate was not affected by CAPs exposure. These results suggest that exacerbation of myocardial ischemia during coronary artery occlusion may be an important mechanism of environmentally related acute cardiac events.     

Choroid Plexus Tumors: Experience of 10 Cases with Special References to Adult Cases

Choroid plexus tumors (CPTs) are rare intraventricular neoplasms accounting for about 0.3–0.6% of all intracranial tumors. This retrospective study on CPTs presents clinico-pathological features and management strategies based on a 20-year single-institutional experience. This series included 10 consecutive patients with pathologically proven CPTs; 5 choroid plexus papillomas (CPPs), 3 atypical CPPs (ACPPs), and 2 choroid plexus carcinomas (CPCs). Their clinical, radiological, and histopathological features as well as management including follow-up studies were reviewed. The patients included five males and five females, aging from 0 years to 61 years with median of 28 years. The affected site was lateral ventricle in two adults and fourth ventricle in eight patients; four children and four adults. The most common symptoms were gait disturbance and memory disturbance. All the patients underwent craniotomy with total, subtotal, and partial removals achieved in 50%, 40%, and 10% of the patients, respectively. The occurrence of the high grade subtypes was 50% in both the adult and pediatric groups. The Ki-67/MIB-1 index increased across the three histological subtypes, from CPP to ACPP and then to CPC. Adjuvant therapy was administered in three patients. The two patients (one adult and one child) with CPC died of whole central nervous system dissemination. At a median of 62-month follow-up, the other eight patients were alive, with only one patient having recurrence and reoperation. The results demonstrate that gross total resection is usually curative for CPP and ACPP, and adjuvant chemoradiotherapy would be required for CPC and incompletely resected ACPP.     

Lactose-conjugated polyion complex micelles incorporating plasmid DNA as a targetable gene vector system: their preparation and gene transfecting efficiency against cultured HepG2 cells.

alpha-Lactosyl-poly(ethylene glycol)-poly(2-(dimethylamino)ethyl methacrylate) block copolymer (lactose-PEG-PAMA) was synthesized to construct a PIC micellar-type gene vector potentially useful for selective transfection of hepatic cells. Lactose-PEG-PAMA spontaneously formed a polyion complex (PIC) micelle with plasmid DNA (pDNA) encoding luciferase (pGL3-Luc) in aqueous solution without any precipitate formation. The lactosylated PIC micelle thus prepared achieved substantially higher transfection efficiency compared to the control PIC micelle without lactose moieties against HepG2 cells possessing asialoglycoprotein (ASGP) receptors recognizing the beta-d-galactose residue. This pronounced transfection efficacy of the lactosylated PIC micelle was inhibited by the addition of excess asialofetuin (ASF), a natural ligand against the ASGP receptor, indicating ASGP receptor-mediated endocytosis to be a major route of the cellular uptake of the lactosylated micelles. Notably, the lactosylated PIC micelle revealed enhanced transfection compared to the control PIC micelle at a lower dose of pDNA, demonstrating the feasibility of using the ligand-conjugated PIC micellar vector for gene delivery to targeted cells.     

Immunoadsorption therapy for neuromyelitis optica spectrum disorders long after the acute phase

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute‐phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti‐aquaporin‐4‐positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice. J. Clin. Apheresis 30:43–45, 2015. © 2014 Wiley Periodicals, Inc.