Immune microenvironment of hepatocellular carcinoma,intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications

Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non-immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non-immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor-targeting immunotherapy.     

Changes of cancer diagnosis disclosure to children in Japan in the last 20 years

International Journal of Clinical Oncology - The practice of cancer diagnosis disclosure to children has been changed with the times. The regulations of clinical trials in the 2000s might change...     

Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.     

Voluntary ambulation using voluntary upper limb muscle activity and Hybrid Assistive Limb® (HAL®) in a patient with complete paraplegia due to chronic spinal cord injury: A case report

Context: We sought to describe our experience with the Hybrid Assistive Limb® (HAL®) for active knee extension and voluntary ambulation with remaining muscle activity in a patient with complete paraplegia after spinal cord injury.

Findings: A 30-year-old man with complete paraplegia used the HAL® for 1 month (10 sessions) using his remaining muscle activity, including hip flexor and upper limb activity. Electromyography was used to evaluate muscle activity of the gluteus maximus, tensor fascia lata, quadriceps femoris, and hamstring muscles in synchronization with the Vicon motion capture system. A HAL® session included a knee extension session with the hip flexor and voluntary gait with upper limb activity. After using the HAL® for one month, the patient’s manual muscle hip flexor scores improved from 1/5 to 2/5 for the right and from 2/5 to 3/5 for the left knee, and from 0/5 to 1/5 for the extension of both knees.

Conclusion/clinical relevance: Knee extension sessions with HAL®, and hip flexor and upper-limb-triggered HAL® ambulation seem a safe and feasible option in a patient with complete paraplegia due to spinal cord injury.     

Interaction of nicotinic acetylcholine receptors with dopamine receptors in synaptic plasticity of the mouse insular cortex

The insular cortex plays essential roles in nicotine addiction. However, much is still unknown about its cellular and synaptic mechanisms responsible for nicotine addiction. We have previously shown that in layer 5 pyramidal neurons of the mouse insular cortex, activation of the nicotinic acetylcholine receptors (nAChRs) suppresses synaptic potentiation through enhancing GABAergic synaptic transmission, although it enhances both glutamatergic and GABAergic synaptic transmission. In the present study, we examined whether dopamine receptors might contribute to the nicotine‐induced inhibition of synaptic potentiation. The nicotine‐induced inhibition of synaptic potentiation was decreased in the presence of a D1 dopamine receptor antagonist SCH23390 irrespective of the presence of a D2 dopamine receptor antagonist sulpiride, suggesting that D1 dopamine receptors are involved in nicotine‐induced inhibition. We also investigated how dopamine receptors might contribute to the nAChR‐induced enhancement of glutamatergic and GABAergic synaptic transmission. The nAChR‐induced enhancement of GABAergic synaptic transmission was decreased in the presence of SCH23390 irrespective of the presence of sulpiride, whereas that of glutamatergic synaptic transmission was not altered in the presence of SCH23390 and sulpiride. These results suggest that D1 dopamine receptors are involved in the nAChR‐induced enhancement of GABAergic synaptic transmission while dopamine receptors are not involved in that of glutamatergic synaptic transmission. These observations indicate that the interaction between nAChRs and D1 dopamine receptors plays critical roles in synaptic activities in layer 5 pyramidal neurons of the mouse insular cortex. These insular synaptic changes might be associated with nicotine addiction.     

Significance of intraoperative monitoring of arterial blood flow velocity and hepatic venous oxygen saturation for performing minimally invasive surgery in a patient with multiple calcified pancreaticoduodenal aneurysms with celiac artery occlusion

Even for patients with multiple pancreaticoduodenal aneurysms, successful treatment with noninvasive operative procedures can be employed, if intraoperative devices are considered. A 73‐year‐old man, without any symptoms, was admitted to our hospital and had computed tomography (CT) scanning to examine his liver for hepatitis C virus (HCV). Selective superior mesenteric artery (SMA) angiography confirmed multiple aneurysms in the anterior inferior pancreaticoduodenal artery (AIPDA), one aneurysm in the posterior inferior mesenteric artery (PIPDA), and another in the occluded celiac trunk, all with severe calcification. All of the aneurysms were thought to communicate with each other. With the celiac artery occlusion, the right hepatic artery (RHA) was revealed to be supplied by collateral arteries from the aneurysms in the AIPDA, and the left hepatic artery was shown to be supplied by collaterals from the left gastric artery. Intraoperative Doppler echography, at the time of the clamping of both IPDAs, demonstrated a marked decrease of blood velocity in all aneurysms (before clamping, >50 cm/s; after, <10 cm/s), although loss of pulsation and a marked decrease of flow in the RHA were inevitable. Therefore, each of these two IPDAs were ligated on the proximal side to the aneurysm, thus preserving the blood flow of the pancreas head fed by the PIPDA; bypass grafting from the AIPDA to the RHA, using the great saphenous vein, was done at the same time. After the creation of an anastomosis, the hepatic venous oxygen saturation (ShvO2) increased from 38% (at the time of ligation of the IPDAs) to 57% under ventilation. The patient's postoperative clinical course was uneventful. We describe and discuss our successful noninvasive operative management of multiple pancreaticoduodenal aneurysms, done while monitoring the blood flow and ShvO2, with some consideration of the literature.     

Influence of SNPs in cytokine-related genes on the severity of food allergy and atopic eczema in children

Although many single nucleotide polymorphism (SNP) studies have reported an association of atopy, allergic diseases and total serum immunoglobulin E (IgE) levels, almost all of these studies sought risk factors for the onset of these allergic diseases. Furthermore, many studies have analyzed a single gene and hardly any have analyzed environmental factors. In these analyses, the results could be masked and the effects of other genes and environmental factors may be decreased. Here, we described the correlation between four genes [interleukin (IL)-4 (C-590T), IL-4 receptor (A1652G), FCER1B (G6842A) and STAT6 (G2964A)] in connection with IgE production; the role of IL-10 (C-627A) as a regulatory cytokine of allergy; and the severity of food allergy (FA) and atopic eczema (AE) in 220 Japanese allergic children. In addition to these SNPs, environmental factors, i.e., patient's attitude, indoor environment, and so on, were also investigated in this study. Our study was retrospective, and the correlation was analyzed by our defined clinical scores divided into three terms: worst symptoms, recent symptoms and general amelioration at the most recent examination during the disease course. Our results indicated that IL-10 AA, the genotype with lower IL-10 production, is associated with higher IgE levels in the serum (p < 0.0001, estimate; 0.912). Marginal liver abnormalities were observed in the subject group with both FA and AE (p < 0.1191, estimate; 0.1490). Our defined clinical scores enabled evaluation of various aspects of disease severity. Based on the scores, while no single SNP selected in this study determined severity, the combination of the SNP with laboratory data and environmental factors appeared to determine severity.     

Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension.

The phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, has been reported to produce sustained pulmonary vasodilatation in patients with pulmonary hypertension (PH). Recently, vardenafil, a more potent and selective PDE-5 inhibitor than sildenafil, has been approved for the treatment of erectile dysfunction. However, the long-term effects of oral vardenafil in patients with PH are unknown. We studied five consecutive patients with PH; one with primary pulmonary hypertension, two with chronic pulmonary thromboembolism, one with Eisenmenger syndrome (ventricular septal defect) and one with secondary pulmonary hypertension after a ventricular septal defect closure operation. In an acute hemodynamic trial, vardenafil (5 mg) significantly decreased both the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) with an increase in cardiac output. In a chronic hemodynamic trial, the maintenance dose of vardenafil (10 to 15 mg) for 3 months significantly decreased the PVR, but not the SVR, with a 20.7% reduction of the PVR/ SVR ratio. Plasma brain natriuretic peptide (BNP) levels were also significantly decreased after 3 months. This pilot study demonstrates that long-term oral vardenafil therapy may be a safe and effective treatment for patients with PH.     

A case report: Severe bone marrow suppression caused by 6-mercaptopurin in Crohn's disease patient]

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/microl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.     

LONG‐TERM FOLLOW UP OF PATIENTS WITH SMALL GASTROINTESTINAL STROMAL TUMORS IN THE STOMACH USING ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED FINE‐NEEDLE ASPIRATION BIOPSY

Background: Gastrointestinal stromal tumors (GIST) are one of the most common mesenchymal tumors of the gastrointestinal tract. GIST are defined by positive immunohistochemical staining for KIT or CD34 and thus are generally diagnosed after surgery. Because small GIST are rarely diagnosed before surgery, the clinical course of these small tumors is not clear. The aim of the present study was to follow changes in size and configuration of small GIST that were pathologically confirmed using endoscopic ultrasonography‐guided fine‐needle aspiration biopsy (EUS‐FNAB). Methods: Between July 1997 and December 2003, 16 tumors in 16 patients (10 men and 6 women) with an immunohistochemical diagnosis of GIST were regularly followed in our hospital. The median patient age when EUS‐FNAB was performed was 62 years (range 26–82 years) and the median follow‐up period was 4.9 years (range 0.5–9.6 years). Results: Fourteen tumors showed no remarkable changes in size and shape during follow up compared with the initial diagnosis. Two tumors enlarged: one tumor approximately doubled its diameter in 8 years and the other tumor increased from 1.8 cm at diagnosis to up to 10 cm after only 2 years. Doubling time of the latter tumor was calculated as 3.1 months. Conclusions: We conclude that EUS‐FNAB might be a good modality for final diagnosis of GIST without surgery, and that GIST without rapid growth on follow up can be endoscopically followed.