1: Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification

HEPATOLOGY

SEP 2018, 68 (3):1025-1041; DOI: 10.1002/hep.29904

Yutaka Kurebayashi, Hidenori Ojima, Hanako Tsujikawa, Naoto Kubota, Junki Maehara, Yuta Abe, Minoru Kitago, Masahiro Shinoda, Yuko Kitagawa, Michiie Sakamoto

With the widespread use of immune checkpoint inhibitors, research on anti-tumor immunity is actively being conducted; however, there have been few studies that directly and comprehensively observe the combinations in which immune cells infiltrate tumors. Therefore, we attempted to classify the immune microenvironment of hepatocellular carcinoma by combining multiplex immunohistochemistry and cluster analysis. This revealed that the immune microenvironment of hepatocellular carcinoma can be broadly classified into three types, and that hepatocellular carcinomas belonging to the "Immune-high" group, characterized by B-cell/plasma cell infiltration in addition to T-cell infiltration, have a very good prognosis. Interestingly, the Immune-high group was relatively concentrated in poorly differentiated hepatocellular carcinomas, which are considered to have a poor prognosis. We also found that even among poorly differentiated hepatocellular carcinomas and CK19-positive hepatocellular carcinomas, which are even stronger poor prognostic factors, those belonging to the Immune-high group had a good prognosis. Furthermore, using the fact that hepatocellular carcinoma is a good model for multistep carcinogenesis, we showed that the tumor immune microenvironment changes stepwise along with the process of multistep carcinogenesis. We believe these results reaffirm the significance of pathologically evaluating the immune microenvironment and indicate the need for functional analysis of B-cells/plasma cells infiltrating human tumors.

(Michiie Sakamoto, Professor, Department of Pathology, 64th;

Yutaka Kurebayashi, Assistant Professor, Department of Pathology (currently Visiting Fellow at the National Cancer Institute, USA), 90th)

Biol Psychiatry.

2018 Sep 26. pii: S0006-3223(18)31852-3. doi: 10.1016/j.biopsych.2018.09.009.

Yusuke Iwata, Shinichiro Nakajima, Eric Plitman, Fernando Caravaggio, Julia Kim, Parita Shah, Wanna Mar, Sofia Chavez, Vincenzo De Luca, Masaru Mimura, Gary Remington, Philip Gerretsen, Ariel Graff-Guerrero

Schizophrenia is a disorder that affects about 1% of the total population and is accompanied by a significant decline in social functioning, with hallucinations and delusions as prominent symptoms. The mainstay of drug treatment for schizophrenia is antipsychotics with dopamine-blocking effects, but about 30% of patients do not respond to treatment. It has been reported that these treatment-resistant patients have dopamine synthesis capacity comparable to that of healthy individuals, and clozapine, the only effective antipsychotic for treatment-resistant patients, has weak dopamine-blocking effects. In recent years, studies using magnetic resonance spectroscopy (MRS) have repeatedly reported high glutamate concentrations in the anterior cingulate cortex of treatment-resistant patients, suggesting that the pathophysiology of treatment-resistant patients may be based on abnormalities in glutamatergic neurotransmission. This study examined glutamate concentrations in the anterior cingulate cortex in 26 clozapine-resistant patients, 27 clozapine-responsive patients, 21 patients responsive to non-clozapine treatment, and 26 healthy individuals. As a result, we revealed that glutamate concentrations in the anterior cingulate cortex of clozapine-resistant patients were higher compared to healthy individuals. We are currently conducting a study using MRS to examine changes in brain glutamate concentrations before and after the introduction of clozapine. This research is expected to open up new avenues for treatment in treatment-resistant patients.

(Yusuke Iwata, Department of Neuropsychiatry, 87th equivalent; Shinichiro Nakajima, 81st; Masaru Mimura, 63rd)

IMMUNOLOGICAL REVIEWS,

286 (1):37-52;DOI: 10.1111/imr.12706 NOV 2018

Hiroki Kabata, Kazuyo Moro, Shigeo Koyasu