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.     

Hair shaft miRNA‐221 levels as a new tumor marker of malignant melanoma

miRNA‐221 (miR‐221) is known to be abnormally expressed in many human cancers. The serum levels of miR‐221 have been reported as a tumor marker for malignant melanoma (MM). We hypothesized that the hair shaft miR‐221 levels may be increased in patients with MM. We therefore assessed the possibility that hair shaft miR‐221 levels could be a marker for MM. The hair shaft miR‐221 levels were significantly higher in patients with MM than controls. The rates of increased hair shaft miR‐221 levels above the cut‐off value were comparable to those of serum 5‐S‐CD, which is a tumor marker commonly used for MM. Measurements of the hair shaft miR‐221 levels could have potential clinical value in the detection of MM. This is the first report investigating the hair shaft levels of an miRNA in patients with MM. Our investigations offer new insight into the relationship between miR‐221 and MM, and may provide a new, non‐invasive way to screen for melanoma.     

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.     

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.     

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.     

Desmoglein, the target molecule in autoimmunity and infection]

To form the human body and maintain the integrity of its complex tissues, individual cells need to hold tightly to each other. The desmosome is the major type of intercellular adhesive junction, and has desmoglein (Dsg), a cadherin type cell-cell adhesion molecule, as a transmembrane component. Dsg is now known to be targeted in autoimmune diseases, infectious diseases, as well as inherited diseases. Patients with pemphigus, an autoimmune blistering disease of the skin and mucous membrane, have IgG autoantibodies directed against Dsg1 and Dsg3. A subset of patients with pemphigus have Dsg1/Dsg4 crossreacting IgG autoantibodies. Exfoliative toxins produced by Staphylococcal aureus, which causes Staphylococcal Scalded Skin Syndrome (SSSS) and bullous impetigo, specifically digest Dsg1. A subset of patients with SSSS develop a low titer of anti-Dsg1 IgG autoantibodies. A mutation in DSG1 gene causes striate palmoplantar keratoderma and a mutation in DSG4 gene causes inherited hypotrichosis. It is not clear why so many diseases are clustered in desmogleins, but there must be a reason for this. Studies on desmogleins will provide an important framework to understand the mysteries between autoimmunity and infection.     

The effect of metronidazole on TPN-associated liver dysfunction in neonates

The effect of metronidazole (MNZ) on hepatic dysfunction associated with total parenteral nutrition (TPN) in neonates was investigated. Neonates receiving TPN for more than 2 weeks were divided into three groups. In group 1, TPN was given alone, in group 2, 25 mg/kg/d of MNZ was administered intravenously for the first 2 weeks of TPN, and in group 3, 50 mg/kg/d of MNZ was given for the first 3 weeks of TPN. Several parameters of liver function tests (LFTs) during the first 4 weeks of TPN were compared among these three groups. There was no significant difference of these parameters between group 1 and group 2. Although there was no significant difference of alkaline phosphatase, gamma-glutamyl transpeptidase, direct bilirubin, and total bile acid between groups 1 and 3, transaminase (glutamic oxaloacetic, glutamic pyruvic) of group 3 remained significantly lower than those of group 1. In conclusion, the administration of MNZ 50 mg/kg/d for 3 weeks, at least, prevented the elevation of transaminase during TPN in neonates, suggesting the possible involvement of intestinal anaerobic flora in the pathogenesis of TPN-associated liver dysfunction.     

Monoclonal antibody analysis of glomerular, tubulo-interstitial infiltrating immune cells in various glomerulonephritis

To investigate the role of cell-mediated immunity (CMI) in glomerulonephritis (GN), we identified the infiltrating immune cells both within the glomerulus and in the interstitium. Frozen sections from 103 patients with various forms of GN: 10 with minor glomerular abnormality (MGA) as control, 10 with minimal change nephrotic syndrome (MCNS), 10 with membranous nephropathy (MN), 9 with focal glomerulosclerosis (FGS), 30 with IgA nephropathy (IgAN), 22 with acute post streptococcal glomerulonephritis (APSGN), and 2 with rapidly progressive glomerulonephritis (RPGN) were examined using monoclonal antibodies (MoAb) by indirect immunoalkaline-phosphatase labelling. In most glomerulonephritis, monocyte/M phi and helper/inducer T cells were predominantly infiltrating in the interstitium, but intraglomerular infiltration was rare, except for APSGN. This interstitial infiltration increased proportionally to the level of serum creatinine, and was most prominent in RPGN. Apparently different distribution was seen in APSGN, that is, prominent increase in total number of intra-glomerular monocyte/M phi infiltration with slightly increased T cells. The change was correlated with time after onset; namely the more leucocytic infiltration was observed when the tissue was taken earlier. These data suggest that in APSGN, monocyte/M phi accumulate in glomeruli via cell mediated immunity in addition to humoral immune mechanism resulting in glomerular hypercellularity, whereas in most chronic glomerulonephritis interstitial leucocyte infiltration, particularly helper T cells and monocyte/M phi may play an important role in the progression of glomerulonephritis.