Current status of treatment with immune checkpoint inhibitors for gastrointestinal, hepatobiliary, and pancreatic cancers

The development of immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death protein ligand 1 (PD-L1) has revolutionized the treatment strategy in various types of cancers. In addition, recent studies have revealed that tumor microsatellite instability (MSI) status and tumor mutation burden (TMB) contribute significantly to the therapeutic response to anti-PD-1 monoclonal antibody (mAb), which led to an accelerated approval to pembrolizumab for the treatment of MSI-high or mismatch-repair-deficient solid tumors after conventional chemotherapies in 2017 and for the treatment of TMB-high solid tumors in 2020 by the United States Food and Drug Administration (FDA). In the field of gastrointestinal cancers, many clinical trials evaluating the safety and efficacy of various regimens such as ICI monotherapy, the combination of anti-CTLA-4 mAb and anti-PD-1/PD-L1 mAb, and combination of ICI and conventional chemotherapy or tyrosine kinase inhibitor have been reported or are in progress. This review summarizes MSI status and TMB in gastrointestinal, hepatobiliary, and pancreatic cancers, and provides the results of most relevant clinical trials evaluating ICIs. We also discuss the development of biomarkers required for improving the selection of patients with a high probability of benefiting from treatment with ICIs, and potential therapeutic strategies that could help to enhance anticancer responses of ICIs

Antigenicity of chlorpromazine and clozapine to rabbits

Antigenicity of clozapine was studied in rabbits, comparing with that of chlorpromazine as control. The results indicate that chlorpromazine produces antibody in rabbit as revealed by passive hemagglutination test, giving the titer of 1 : 2, 000 or higher in all the five cases observed, though specific precipitin lines has not been obtained and PCA test proves to be negative. Clozapine failed to produce anti.clozapine antibody giving negative passive hemagglutination test, passive cutaneous anaphylaxis and precipitin reaction, in all forms tested. Some remarks were made on the possible close relation between the antigenicity of the drug and its affinity to protein.</p

A new method for counting the reticulocyte number

The counting of reticulocyte number by the routine method on the dye fillms often leads to a poor result. This can be avoided by counting them on the collodion dye film on which the almost equal distribution of reticulocytes can be attained.</p

Risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease-associated hepatocellular carcinoma: Current evidence and future perspectives

High rates of excessive calorie intake diets and sedentary lifestyles have led to a global increase in nonalcoholic fatty liver disease (NAFLD). As a result, this condition has recently become one of the leading causes of hepatocellular carcinoma (HCC). Furthermore, the incidence of NAFLD-associated HCC (NAFLD-HCC) is expected to increase in the near future. Advanced liver fibrosis is the most common risk factor for NAFLD-HCC. However, up to 50% of NAFLD-HCC cases develop without underlying liver cirrhosis. Epidemiological studies have revealed many other risk factors for this condition; including diabetes, other metabolic traits, obesity, old age, male sex, Hispanic ethnicity, mild alcohol intake, and elevated liver enzymes. Specific gene variants, such as single-nucleotide polymorphisms of patatin-like phospholipase domain 3, transmembrane 6 superfamily member 2, and membrane-bound O-acyl-transferase domain-containing 7, are also associated with an increased risk of HCC in patients with NAFLD. This clinical and genetic information should be interpreted together for accurate risk prediction. Alpha-fetoprotein (AFP) is the only biomarker currently recommended for HCC screening. However, it is not sufficiently sensitive in addressing this diagnostic challenge. The GALAD score can be calculated based on sex, age, lectin-bound AFP, AFP, and des-carboxyprothrombin and is reported to show better diagnostic performance for HCC. In addition, emerging studies on genetic and epigenetic biomarkers have also yielded promising diagnostic potential. However, further research is needed to establish an effective surveillance program for the early diagnosis of NAFLD-HCC

Allergic inflammation, its development mechanism and per­meability of cell membrane

The ascitic monocytes and subcutaneous cells and tissues of sensitized animals have been observed after exposing to antigen for the purpose of revealing the disintegration processes of the cells related with inflammation and it has been proved that the permeability of the cell membrane increases markedly resulting in the swelling of the cells at the moment when the cells come in contact with antigen. The localization of the antigen in the Arthus' phenomenon will be the results of the gelatination of the inter-cellular tissues and the swelling of cells. And it is indicated that the cell death accompanied by an allergic inflammation is caused by the increased permeability of the cell membrane which will result in the activation of the intra-cellular enzymes followed by the acute disintegration of the molecular structure of the cell and release of the so-called inflammatory substances.</p

The role of the SWI/SNF chromatin remodeling complex in pancreatic ductal adenocarcinoma

ATP-dependent chromatin remodeling complexes are a group of epigenetic regulators that can alter the assembly of nucleosomes and regulate the accessibility of transcription factors to DNA in order to modulate gene expression. One of these complexes, the SWI/SNF chromatin remodeling complex is mutated in more than 20% of human cancers. We have investigated the roles of the SWI/SNF complex in pancreatic ductal adenocarcinoma (PDA), which is the most lethal type of cancer. Here, we reviewed the recent literature regarding the role of the SWI/SNF complex in pancreatic tumorigenesis and current knowledge about therapeutic strategies targeting the SWI/SNF complex in PDA. The subunits of the SWI/SNF complex are mutated in 14% of human PDA. Recent studies have shown that they have context-dependent oncogenic or tumor-suppressive roles in pancreatic carcinogenesis. To target its tumor-suppressive properties, synthetic lethal strategies have recently been developed. In addition, their oncogenic properties could be novel therapeutic targets. The SWI/SNF subunits are potential therapeutic targets for PDA, and further understanding of the precise role of the SWI/SNF complex subunits in PDA is required for further development of novel strategies targeting SWI/SNF subunits against PDA

Mitochondria and Endoplasmic Reticulum in the Denucleated Red Cells, with Special Reference to the Reticulum of Reticu-locyte

In 1955 SANO found mitochondria by the supravital stain with Janus green B in the basophilic stippled cells from the circulating blood of the lead intoxicated rabbitsl , and in 1956 by means of electronmicroscope VALLEJO-FREIRE, BRUNNER et al. found mitochondria in the reticulocytes2,3, and later at the end of 1956 BRAUNSTEINER et al. also succeeded in revealing mitochondria and the vesicular structure by electron microscope in the ultra thin section of young red cells4. We also have found the mitochondria and the endoplasmic reticulum in young red cells. It has been discussed long whether the reticulum of reticulocytes is a preexistent structure or an artifact. The fact that the mitochondria exist in the reticulocyte seems to support strongly the preexistence theory of the reticulum, substantia reticulo filamentosa. However, the fact that the reticulum has several characteristics different from the general mitochondria5,6 can not be ignored. In this paper we should like to demonstrate the photos of mitochondria and the endoplasmic reticulum in the denucleated red cells revealed by electron microscope comparing to the picture of reticuluocyte appeared by supravital stain.</p

Pretreatment neutrophil-to-lymphocyte ratio as a predictive marker of response to atezolizumab plus bevacizumab for hepatocellular carcinoma

Background: Combination therapy with anti-programmed death-ligand 1 monoclonal antibody atezolizumab plus anti-vascular endothelial growth factor agent bevacizumab (Atezo/Bev) was approved in 2020 as a first-line treatment for unresectable hepatocellular carcinoma (HCC). Atezo/Bev therapy is relatively well tolerated; however, factors that can predict its response have not yet been reported. Thus, we aimed to investigate whether the pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict the therapeutic response in patients with HCC treated with Atezo/Bev therapy. Methods: We analyzed the course of 40 patients with HCC who received Atezo/Bev therapy at our hospital and attempted to identify pretreatment factors that could predict response by comparing those who achieved disease control with those who did not. Results: The pretreatment NLR value in patients who achieved disease control was significantly lower than that in patients with disease progression (2.47 vs. 4.48, p = 0.013). Using the optimal NLR cut-off value for predicting response (3.21) determined by receiver operating characteristic curve analysis, patients with NLR ≤ 3.21 had significantly better progression-free survival than those with NLR > 3.21 (p < 0.0001), although there were no significant differences in liver function or tumor-related background factors between the two groups. Conclusions: The pretreatment NLR value may be a useful predictor of response to Atezo/Bev therapy for HCC