Anti-PD1 checkpoint inhibitor therapy in acral melanoma: a multicenter study of 193 Japanese patients.

BACKGROUND: Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM. PATIENTS AND METHODS: We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies. RESULTS: In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03). CONCLUSIONS: Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

Changes in standing body sway of pregnant women after long-term bed rest.

Pregnant women tend to fall and increased body postural instability, namely body sway, may be one of the causative factors. We had a clinical impression that pregnant women after long-term bed rest tend to fall. We hypothesised that such women may show increased body sway, which we attempted to determine. Pregnant women (n = 161) were divided into three groups: (i) women with preterm labour after 2-week bed rest, (ii) those after 4-week bed rest, and (iii) those without bed rest or preterm labour. Body sway was analysed using stabilometry, that is, computed analysis of movement of the centre of gravity. The 3 groups fundamentally showed the same stabilometric measurements. Women with oedema showed greater medial-lateral sway than those without it. Factors other than oedema yielded no differences in stabilometric parameters. Long-term bed rest fundamentally did not increase body sway to the extent that stabilometry could reveal it. It may be prudent to consider that pregnant women with oedema tend to fall.

Effect of high- and low-energy entrance surface dose allocation ratio for two-shot dual-energy subtraction imaging on low-contrast resolution.

INTRODUCTION: Dual-energy subtraction (DES) imaging can obtain chest radiographs with high contrast between nodules and healthy lung tissue, and evaluating of chest radiography and evaluating exposure conditions is crucial to obtain a high-quality diagnostic image. This study aimed to investigate the effect of the dose allocation ratio of entrance surface dose (ESD) between high- and low-energy projection in low-contrast resolution of soft-tissue images for two-shot DES imaging in digital radiography using a contrast-detail phantom (CD phantom). METHODS: A custom-made phantom mimicking a human chest that combined a CD phantom, polymethylmethacrylate square plate, and an aluminum plate (1-3 mm) was used. The tube voltage was 120 kVp (high-energy) and 60 kVp (low-energy). The ESD was changed from 0.1 to 0.5 mGy in 0.1 mGy increments. Dose allocation ratio of ESD between 120 kVp and 60 kVp projection was set at 1:1, 1:2, 1:3, and 2:1. Inverse image quality figure (IQFinv) was calculated from the custom-made phantom images. RESULTS: When the total ESD and aluminum thickness were constant, no significant difference in IQFinv was observed under most conditions of varied dose allocation ratio. Similarly, when the total ESD and the dose allocation ratio were constant, there was no significant difference in IQFinv based on the aluminum plate thickness. CONCLUSION: Using IQFinv to evaluate the quality of the two-shot DES image suggested that dose allocation ratio did not have a significant effect on low-contrast resolution of soft-tissue images. IMPLICATIONS FOR PRACTICE: The present results provide useful information for determining exposure conditions for two-shot DES imaging.

Amiodarone-induced liver cirrhosis and parkinsonism: a case report.

BACKGROUND: Amiodarone-induced hepatotoxicity consists of mild liver test abnormalities and rare cases of acute hepatitis and chronic hepatic lesions, and histologically resembles the whole spectrum of alcoholic liver disease, i.e., non-alcoholic steatohepatitis. Amiodarone-induced neurotoxicity, including tremor, ataxia and peripheral neuropathy, is known, and some cases of parkinsonism following amiodarone use have also been reported. OBJECTIVE: To study the pathology of amiodarone-associated parkinsonism. DESIGN: Light and electromicroscopic examinations of a patient with liver cirrhosis and amiodarone-induced parkinsonism. RESULTS: On postmortem examination, the liver showed micronodular cirrhosis. Striking steatosis and frequent Mallory bodies were present on light microscopy. There were lysosomal inclusion bodies on electron microscopy. From these findings, amiodarone-induced liver cirrhosis was diagnosed. Brain atrophy and infarcts were not observed, and pigmentation in the substantia nigra was preserved. Histologically, there was a slightly lesser degree of neuronal loss with astrocytosis in the substantia nigra, locus ceruleus, and dorsal vagal nucleus. Lewy bodies were not found. In the cerebral white matter and basal ganglia, Alzheimer Type II astrocytes, which are abundant in hepatic encephalopathy, had deposition of electron-dense materials within the lysosomes and mitochondrial matrices. The materials were compatible with the accelerated amiodarone. CONCLUSIONS: This is the first case in which the accumulation of amiodarone in the brain was morphologically observed. Amiodarone accumulation in the brain may play a role in neurotoxicity inducing parkinsonism.

Hyperkalemia in both surgically and medically treated patients with primary aldosteronism.

Hyperkalemia is an important complication of adrenalectomy for patients with primary aldosteronism (PA). The frequency of hyperkalemia after medication using mineralocorticoid receptor antagonists (MRAs) for PA is unclear. The aim of this study is to investigate the frequency and the risk factors of hyperkalemia after surgery and medication for PA. The data of 376 patients with PA registered in a multicentre-collaborative study in Japan, including surgically treated patients (group A; n=142) and medically treated patients with MRAs (group B; n=234) were studied. The prevalence of hyperkalemic patients (serum potassium >5.0 mEq l-1) after treatment was higher in group A than group B (9.9 vs 3.8%, P<0.01). At diagnosis, the hyperkalemic patients were older and had a poorer renal function than the non-hyperkalemic patients in both groups (P<0.05). The hyperkalemic patients had severer PA in group A and milder PA in group B. The independent risk factor by a logistic regression analysis was only age in both groups. After treatment, the percentages of patients withdrawing antihypertensive drugs and the normalization of aldosterone renin ratio were not different between hyperkalemic and non-hyperkalemic patients in group A. The type and dose of MRAs and the combination of other antihypertensive drugs were not different between hyperkalemic and non-hyperkalemic patients in group B. In conclusion, the potential occurrence of hyperkalemia should be considered after medical as well as surgical treatment for PA, especially in patients with older age (>60 years) and impaired renal function (estimated glomerular filtration rate <70 ml min-1 per 1.73 m2) at diagnosis.

Highly selective aldose reductase inhibitors. 1. 3-(Arylalkyl)-2,4,5-trioxoimidazolidine-1-acetic acids.

A series of 3-(arylalkyl)-2,4,5-trioxoimidazolidine-1-acetic acids (1) was prepared and tested for aldose reductase (AR) and aldehyde reductase (ALR) inhibitory activities. These compounds showed strong inhibitory activity against AR without significant inhibitory activity for ALR. The ratio of IC50(ALR)/IC50(AR) was > 1000 in some compounds. On the basis of pharmacological tests such as the recovery of reduced motor nerve conduction velocity and toxicological profile, 3-(3-nitrobenzyl)-2,4,5-trioxoimidazolidine-1-acetic acid (NZ-314) was selected as the candidate for clinical development.

Factor XII-dependent contact activation on endothelial cells and binding proteins gC1qR and cytokeratin 1.

Although proteins of the kinin-forming pathway are bound along the surface of endothelial cells, the mechanism of activation of this proteolytic cascade is unclear. Endothelial cell surface proteins, gC1qR and cytokeratin 1, are capable of binding Factor XII and high molecular weight kininogen (HK) in a zinc-dependent reaction thus we considered the possibility that these proteins might catalyze initiation of the cascade. Incubation of Factor XII, prekallikrein, and HK with gC1qR or cytokeratin 1 leads to a zinc-dependent and Factor XII-dependent conversion of prekallikrein to kallikrein. We also demonstrate that normal plasma is capable of activating upon interaction with the cells whereas plasma deficient in Factor XII, prekallikrein and HK do not activate. Normal plasma activation was inhibitable by antibody to gC1qR and cytokeratin 1. Thus, gC1qR and cytokeratin 1, represent potential initiating surfaces for activation of the plasma kinin-forming cascade and may do so as a result of their expression along cell surfaces.

Effect of neurotropin on the binding of high molecular weight kininogen and Hageman factor to human umbilical vein endothelial cells and the autoactivation of bound Hageman factor.

Bradykinin is generated by activation of the plasma kallikrein-kinin (K-K) cascade and contributes to the symptoms of allergic reactions and the perception of pain. Neurotropin is a biological material obtained from inflamed rabbit skin inoculated with vaccinia virus, which is widely used clinically in Japan as an effective agent for these disorders. Factor XII (FXII) and high molecular weight kininogen (HK), two critical constituents of the plasma K-K cascade, bind to endothelial cells, and bound FXII is autoactivated in the presence of zinc ions. We have investigated the effects of Neurotropin on the interactions of FXII and HK with endothelial cells. Neurotropin inhibited the binding of both proteins to cultured human umbilical vein endothelial cells (HUVEC) and inhibited autoactivation of FXII upon HUVEC in a concentration-dependent manner. These data suggest that the ameliorating effects of Neurotropin in allergic disorders and pain syndromes may be related to this ability to inhibit activation of the K-K cascade and, consequently, the formation of bradykinin.

Disordered magnetism at the metal-insulator threshold in nano-graphite-based carbon materials

The magnetism of activated carbon fibers composed of a disorder network of nanographites was investigated, where each nanographite has about 1 edge-inherited localized spin. The susceptibility, for samples situated around the metal-insulator threshold, shows a cusp around 4-7 K in addition to the presence of a field-cooling effect. These behaviors are explained in terms of disordered magnetism caused by random strengths of inter-nano-graphite antiferromagnetic interactions mediated by pi-conduction carriers.

Interruption of pulmonary arterial flow with inadequate ventilation leads to pulmonary infection.

We examined the effect of interruption of pulmonary arterial flow and inadequate ventilation on the development of pulmonary infarction in rats. Pulmonary arterial flow was blocked by the injection of agar into the inferior vena cava and inadequate ventilation was produced by obstructing the left main bronchus with a polypropylene tip. Histological and angiographic examination of the lung demonstrated that: pulmonary artery embolism alone does not induce pulmonary infarction; obstruction of a bronchus does not induce significant changes, but that pulmonary infarction develops when pulmonary artery embolism and obstruction of a bronchus occur simultaneously. It has been thought that pulmonary infarction is caused by acute obstruction of a pulmonary artery, however, the alveolar walls are supplied with oxygen by both the pulmonary circulation and by ventilation. Interruption of pulmonary arterial flow alone is probably not sufficient to induce pulmonary infarction, which is probably caused by deficiency of oxygen supply to the alveolar walls by a synergy between interruption of pulmonary arterial flow and inadequate ventilation.

Adult onset Still's disease with hemophagocytic syndrome and severe liver dysfunction.

We report the case of a 55-year-old Japanese woman with adult onset Still's disease in whom hemophagocytic syndrome and severe liver dysfunction developed. High serum levels of ferritin, macrophage colony stimulating factor and interferon-gamma, which imply the presence of hemophagocytic syndrome, were detected. It is known that hemophagocytic syndrome is associated with adult onset Still's disease. In our case, many markedly swollen Kupffer cells with phagocytized red blood cells were found in the liver, as well as macrophages in the bone marrow and spleen. Accordingly, we believe that severe liver dysfunction in this case may have been related to hypercytokinemia due to hemophagocytic syndrome.

Species variation in pharmacokinetics and opsonization of palmitoyl rhizoxin (RS-1541) incorporated in lipid emulsions.

Highly lipophilic antitumor agent, palmitoyl rhizoxin (RS-1541), was incorporated into stable lipid emulsions about 100-1000nm in mean diameter consisting of triglyceride ODO and surfactant HCO-60. The pharmacokinetics of RS-1541 were studied after i.v. injection in mice, rats, rabbits, and dogs. Dog showed characteristic pharmacokinetics of RS-1541, compared with other species. RS-1541 was much more rapidly eliminated from plasma with emulsion particles in dogs than in mice, rats, and rabbits. Most amounts of injected RS-1541 were recovered in the liver six hours after administration to dogs, while less than 20% recoveries were observed for mice and rats. To clarify this species variation, opsonization of emulsion particles were evaluated. When emulsions (about 200nm in size) were opsonized by dog plasma, and intravenously injected to rats, total clearance and liver uptake of RS-1541 were increased to 1.8 fold and 2.7 fold of control values, respectively. In contrasts, emulsions opsonized by mouse, rabbit and human plasma did not show such drastic changes in pharmacokinetics of RS-1541 in rats. Furthermore, total clearance of RS-1541 for emulsions opsonized by dog plasma was increased to 1.9 fold of controls after injection to rabbits. These results indicate that opsonizing activities of dog plasma for RS-1541 emulsions are high, compared with other species. This species variation in opsonizing process probably caused the species variation in the pharmacokinetics of RS-1541 incorporated in lipid emulsions.

Enhanced hepatotoxicity of endotoxin by hypoxia.

Pathogenesis of hepatic injury often seen in patients with congestive heart failure is obscure, but hepatic hypoxia and endotoxaemia resulting from congestive heart failure may relate to it. The present study was undertaken in rats to ascertain whether hepatic hypoxia potentiates endotoxin-induced hepatotoxicity. Hypoxic condition of hepatocytes ws induced by exposure to 7% oxygen for 3 hours or administration of ethanol. When endotoxin was given immediately before or several hours after hypoxia, elevation of activities of serum transaminases and focal random hepatocellular necrosis in the lobules were induced, although these functional and morphological changes were not observed in rats with hypoxia or endotoxaemia alone. This finding indicates that hepatic hypoxia leads to a potentiation of sensitivity to endotoxin hepatotoxicity which persists for several hours after recovery from hypoxia. Moreover, these experimental data suggest that hepatic injury in patients with congestive heart failure may be caused by enhancement of endotoxin hepatotoxicity by hepatic hypoxia.

On the pathogenesis of hepatic dysfunction and necrosis following acute circulatory failure.

To clarify whether diminished hepatic blood flow and portal endotoxaemia interact in the pathogenesis of hepatic dysfunction secondary to acute circulatory failure, such as shock, prolonged hypotension, or left-sided heart failure, the present study was undertaken in rats. Reduced hepatic perfusion, which was produced by partial obstruction of the portal vein, caused elevation of serum transaminase activities and electron microscopic abnormalities of hepatocytic structure, namely, disruption of plasma membrane, swelling of mitochondria, vesiculation and disruption of endoplasmic reticulum, etc. Portal endotoxaemia, which was induced by infusion of endotoxin into the portal vein, led to a rise of serum transaminase activities and random, focal coagulative hepatocellular necrosis. In contrast, massive hepatic necrosis and excessive elevation of serum transaminase activities, which are similar to those seen in patients with shock, etc., were produced when portal endotoxaemia was superimposed upon poor hepatic perfusion. These experimental results suggest that acute hepatic failure and massive hepatic necrosis secondary to acute circulatory failure may be induced by the coexistence of reduced hepatic blood flow and portal endotoxaemia.

Role of endotoxin on hypoglycaemia in acute hepatic failure. Relationship between hypoglycaemia and hepatic injury following endotoxaemia in diabetic and nondiabetic rats.

To clarify the relation of endotoxaemia to hypoglycaemia and consequent death in acute hepatic failure, the interrelationship between the degree of hepatic injury, blood glucose level and mortality following endotoxaemia were examined in streptozotocin-induced diabetic and nondiabetic rats. Endotoxin hepatotoxicity was not enhanced in diabetic state. Blood glucose level was markedly reduced after endotoxin administration in the nondiabetic rats, and the reduction of blood glucose level closely correlated with the degree of hepatic injury (serum transaminase activities), namely, the more severe the hepatic injury, the lower the blood glucose level. Hypoglycaemia due to endotoxaemia occurred also in the diabetic rats when the hepatic injury was severe, but the reduction of blood glucose level was slight when it was mild. The mortality for endotoxaemia in diabetic rats was significantly lower than that in the nondiabetic rats. These experimental data suggest that endotoxaemia may play a role in the development of hypoglycaemia in acute hepatic failure, and that the diabetic state may lower the mortality for endotoxaemia.

Morphogenesis of vertebral deformities in involutional osteoporosis. Age-related, three-dimensional trabecular structure.

STUDY DESIGN: The relation between the semiquantitative data of alteration in three-dimensional trabecular structure and deformities of the vertebral body was analyzed to clarify the morphogenesis of vertebral deformities in involutional osteoporosis. OBJECTIVES: To evaluate semiquantitatively the age-related alterations of the three-dimensional structure of trabeculae of the vertebral body and to clarify their relation to vertebral deformities in involutional osteoporosis. SUMMARY OF BACKGROUND DATA: Recent studies have shown that bone fractures and deformities in osteoporosis do not depend only on a reduced amount of bone tissue. There is no previous study on the relation between bone deformity and the alterations of the three-dimensional structure of trabeculae. METHODS: The second lumbar vertebrae were removed at autopsy from 25 patients who had no disease predisposing them to secondary osteoporosis and no severe vertebral deformities. The sections of the vertebral body were immersed in sodium hypochlorite solution to corrode the bone marrow. Atrophy of trabeculae and increased spacing between trabeculae were evaluated semiquantitatively under stereoscopic microscopy. The authors examined the relation between the semiquantitative data found in the autopsy vertebrae and the patterns and frequencies of each deformity of the second lumbar vertebrae in 99 patients with involutional osteoporosis. RESULTS: The most frequent vertebral deformity was wedge-shaped vertebrae with compression of the anterosuperior portion, and the alterations of the trabecular structure of the anterosuperior portion were severe and closely related to aging. Severe trabecular alterations with no relation to aging did not necessarily cause vertebral deformity. CONCLUSIONS: Trabecular abnormality, which is significantly correlated with aging, may be the necessary and sufficient condition for vertebral deformities in involutional osteoporosis.

St. John's Wort (Hypericum perforatum) induces overexpression of multidrug resistance protein 2 (MRP2) in rats: a 30-day ingestion study.

St. John's Wort (Hypericum perforatum, SJW) has been used as a herbal medicine for the treatment of depression in oral doses of 900-1050 mg/day in humans. However, the ingestion of SJW was reported to cause interactions with drugs. In the present study, we examined the effects of SJW treatment on the induction of drug transporters and enzymes in rats. An immunoblot analysis was performed to quantify the expression of the transporters and enzymes. SJW was given at a dose of 400 mg/kg/day, since it was reported that 400 mg/kg/day is antidepressant effective dose in rats. When SJW was administered for 10 days, the amounts of multidrug resistance protein 2 (MRP2), glutathione S-transferase-P (GST-P) and cytochrome P450 1A2 (CYP1A2) in the liver were increased to 304%, 252% and 357% of controls, respectively, although the amounts of P-glycoprotein and multidrug resistance protein 1 were not changed. Under the same conditions, an increase of MRP2 in the kidney was not observed. The increase in the levels of each protein was maximal at 10 days after SJW treatment and lasted for at least 30 consecutive days. These results suggest that SJW induces hepatic MRP2, GST-P and CYP1A2 overexpressions, and thus, it could affect drug metabolism, conjugation and disposition.

Activation of human Hageman factor (factor XII) in the presence of zinc and phosphate ions.

Hageman factor (FXII, HF) is a monomeric plasma zymogen that is capable of autoactivation to the serine protease FXIIa in the presence of negatively charged surfaces such as glass, kaolin, ellagic acid and dextran sulfate. FXIIa activates prekallikrein to kallikrein which in turn digests high molecular weight kininogen (HK) to produce the vasoactive peptide bradykinin (BK). Known natural activators of FXII and the contact system include heparin, sulfatides, phospholipids, endotoxin, and urate crystals. We now present evidence that FXII can undergo activation in the presence of phosphate ions (P(i)) and certain divalent metal ions. FXII (1 microgram/ml) and prekallikrein (1 microgram/ml), in HEPES buffered saline, pH 7.4, were incubated with 0-100 mM sodium phosphate, 0-200 microM zinc chloride, and 0.6 mM Chromozym-PK; absorbance at 405 nm was monitored. Graphic analysis of the data indicated reciprocal activation of the two enzymes within 60 min which was dependent upon Zn(II) and P(i). While Ca(II) did not replace Zn(II) as an activator it significantly enhanced Zn(II)- and P(i)-dependent activation of FXII. Maximum activation occurred at 1-10 mM P(i) and approximately 25 microM Zn(II). Co(II), Cu(II) and Ca(II) were negative while Fe(II) was positive in the presence of 1 mM P(i). Cl-, SO4= and CO3=/HCO3- ions were negative when tested in the presence of 50 microM Zn(II). P(i) and Zn(II) ions promoted activation of FXII alone (but not prekallikrein) and the kinetics of this reaction suggested autoactivation. These data therefore suggest that physiological concentrations of P(i) and Zn(II) may be sufficient for a low-level turnover of the contact system in plasma which in turn may be responsible for the background levels of cleaved HK and BK found in normal plasma.

Role of lipid peroxidation in enhancement of endotoxin hepatotoxicity.

The present study was undertaken in the rats to examine whether endotoxin hepatotoxicity is enhanced by increased lipid peroxidation. The rats were given 10 ml of water, corn oil or heated and oxygenated corn oil per kg body weight by stomach tube twice a day for 14 days, and then they were injected physiological saline solution or endotoxin (2 or 2.5 mg per kg body weight) into the tail vein. In the rats pretreated with water or corn oil, the activity of serum glutamic pyruvic transaminase was within the normal limit, and there was no conspicuous morphological change in the liver, except for accumulation of fine fat droplets in few liver cells. On the other hand, in the rats pretreated with heated and oxygenated corn oil, containing a large amount of lipid peroxides, accumulation of small fat droplets in the liver cells and a slight elevation of serum transaminase activity were induced. The challenge with endotoxin (2.5 mg per kg body weight) caused focal hepatocellular coagulative necrosis and a marked elevation of serum transaminase activity, irrespective of the sorts of pretreatment, and there was no significant difference in the biochemical change and the histopathological damage between the rats pretreated with water, corn oil and heated and oxygenated corn oil. These results suggest that increased lipid peroxidation does not contribute to the enhancement of endotoxin hepatotoxicity, although it is thought that carbon tetrachloride and ethanol enhance endotoxin hepatotoxicity by synergism between endotoxin and the chemicals through lipid peroxidation.