Abstract
The effect of the skin–capsular distance (SCD) on the controlled attenuation parameter (CAP) for diagnosis of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD) ...remains unclear. The SCD was measured using B-mode ultrasound, and the CAP was measured using the M probe of FibroScan
®
. According to the indications of the M probe, 113 patients with an SCD of ≤ 25 mm were included in the present study. The association between the SCD and CAP was investigated, and the diagnostic performance of the SCD-adjusted CAP was tested. The SCD showed the most significant positive correlation with the CAP (ρ = 0.329, p < 0.001). In the multiple regression analysis, the SCD and serum albumin concentration were associated with the CAP, independent of pathological liver steatosis. According to the multivariate analysis, two different formulas were developed to obtain the adjusted CAP using the SCD and serum albumin concentration as follows: adjusted CAP (dB/m) = CAP − (5.26 × SCD) and adjusted CAP (dB/m) = CAP − (5.35 × SCD) − (25.77 × serum albumin concentration). The area under the receiver operating characteristic curve for diagnosis of a steatosis score ≥ 2 of adjusted CAP was 0.678 and 0.684 respectively, which were significantly greater than the original CAP (0.621: p = 0.030 and p = 0.024). The SCD is associated with the CAP independent of liver steatosis. Adjustment of the CAP using the SCD improves the diagnostic performance of the CAP in NAFLD.
Purpose
The classic two-stage chemical carcinogenesis in rodents is not directly linked to multistage carcinogenesis in humans. In light of our findings that tumor necrosis factor-α (TNF-α) is an ...endogenous tumor promoter and that TNF-α-inducing protein (Tipα) of
Helicobacter pylori
stimulates progression of cancer and epithelial–mesenchymal transition, we think it is necessary to re-examine the concept of tumor promoter, from chemicals to inflammatory proteins.
Topics and results
This paper begins with “inflammation,” discovered by Virchow, studies of Yamagiwa and Tsutsui, and briefly reviews numerous topics, such as (1) the classic concept of tumor promoter, (2) tumor promotion on mouse skin induced by protein kinase C activators and okadaic acid class compounds, (3) organ specificity of tumor promoters, presenting numerous tumor promoters in various organs, (4) unique tumor promotion induced by inhibitors of protein phosphatases 1 and 2A in mouse skin, rat glandular stomach, and rat liver, (5) the significant role of TNF-α in tumor-promoting inflammation, (6) progression induced by Tipα of
H. pylori
, and (7) enhancement of cancer treatment efficacy with the combination of anticancer drugs and green tea catechins, to inhibit tumor-promoting inflammation.
Conclusion
Human cancer development involves both durable genetic changes caused by carcinogens and proinflammatory cytokines, and simultaneous inflammation in progression induced by proinflammatory cytokines and chemokines.
The tumor necrosis factor-α (TNF-α)-inducing protein
gene family, comprising
membrane protein 1
and
, has been identified as a tumor promoter, contributing to
carcinogenicity. Tipα is a unique
...protein with no similarity to other pathogenicity factors, CagA, VacA, and urease. American
strains cause human gastric cancer, whereas African strains cause gastritis. The presence of Tipα in American and Euro-Asian strains suggests its involvement in human gastric cancer development. Tipα secreted from
stimulates gastric cancer development by inducing TNF-α, an endogenous tumor promoter, through its interaction with nucleolin, a Tipα receptor. This review covers the following topics: tumor-promoting activity of the Tipα family members HP-MP1 and Tipα, the mechanism underlying this activity of Tipα via binding to the cell-surface receptor, nucleolin, the crystal structure of rdel-Tipα and N-terminal truncated rTipα, inhibition of Tipα-associated gastric carcinogenesis by tumor suppressor B-cell translocation gene 2 (
), and new strategies to prevent and treat gastric cancer. Thus, Tipα contributes to the carcinogenicity of
by a mechanism that differs from those of CagA and VacA.
Aim
Recently, FibroScan‐AST (FAST) score was reported to be effective for identifying non‐alcoholic steatohepatitis (NASH) with significant activity and fibrosis in non‐alcoholic fatty liver disease ...(NAFLD). The aim of this study was to confirm the diagnostic accuracy of FAST score of Japanese patients and compare the cut‐off values and diagnostic accuracy between the FibroScan M and XL probes.
Methods
Eighty‐two and 84 patients were included the verification and validation sets, respectively. All patients were diagnosed with NAFLD by biopsy by two central expert pathologists. Liver stiffness measurements and controlled attenuation parameter were carried out, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.
Results
No significant difference existed in FAST score between the M and XL probes (0.489 vs. 0.483, P = 0.187). No significant difference existed in the area under the ROC between the two probes (M, 0.7598; XL, 0.7614; P = 0.958). According to the Youden index, the cut‐off value using the M probe was 0.57 with 68.2% sensitivity and 78.3% specificity. For the XL probe, the cut‐off value was 0.56 with 68.2% sensitivity and 73.3% specificity. To obtain sensitivity and specificity values higher than 90%, cut‐off values of 0.35 and 0.66 were chosen for the M probe and 0.32 and 0.63 were chosen for the XL probe.
Conclusions
There was no significant difference in diagnostic accuracy of FAST score between the FibroScan M and XL probes. The FAST score can be used to identify NASH with significant risk in Japanese patients regardless of probe selection.
The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index ...(PI) for acute- and lymphoma-type ATL (ATL-PI).
In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model.
Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (age, serum albumin, and soluble interleukin-2 receptor sIL-2R) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (P < .001; χ(2) = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ(2) = 74.2, 2 df; log-rank test).
The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.
Purpose
Dealing with variants of unknown significance (VUS) is an important issue in the clinical application of NGS-based cancer gene panel tests. We detected a novel
ERBB2
extracellular domain VUS, ...c.1157A > G p.(E401G), in a cancer gene panel test. Since the mechanisms of activation by
ERBB2
extracellular domain (ECD) variants are not fully understood, we aimed to clarify those mechanisms and the biological functions of
ERBB2
E401G.
Methods
ERBB2
E401G was selected as VUS for analysis because multiple software tools predicted its pathogenicity. We prepared
ERBB2
expression vectors with the E401G variant as well as vectors with S310F and E321G, which are known to be activating mutations. On the basis of wild-type
ERBB2
or mutant
ERBB2
expression in cell lines without
ERBB2
amplification or variants, we evaluated the phosphorylation of human epidermal growth factor receptor 2 and related proteins, and investigated with molecular dynamics (MD) simulation the mechanisms conferred by the variants. The biological effects of
ERBB2
E401G were also investigated, both in vitro and in vivo.
Results
We found that
ERBB2
E401G enhances C-terminal phosphorylation in a way similar to S310F. MD simulation analysis revealed that these variants maintain the stability of the EGFR-HER2 heterodimer in a ligand-independent manner. Moreover,
ERBB2
E401G-transduced cells showed an increased invasive capacity in vitro and an increased tumor growth capacity in vivo.
Conclusion
Our results provide important information on the activating mechanisms of
ERBB2
extracellular domain (ECD) variants and illustrate a model workflow integrating wet and dry bench processes for the analysis of VUS detected with cancer gene panel tests.
Liquid biopsy with circulating free DNA (cfDNA) is a recommended alternative method of re-biopsy. Quality control with cfDNA is indispensable for precise examinations, and it is desirable to achieve ...high-quality cfDNA separation. We investigated two issues: the influence of pre-analytical procedures on cfDNA analysis performed as a routine procedure in a standard clinical laboratory, and the extent of deterioration of cfDNA quality due to long-term storage. Comparisons among blood collection tube types, storage temperatures, and periods of blood separation were performed in terms of cfDNA quantification, cfDNA size distribution, and detection of
mutations. Quality of cfDNA was better with collection tubes containing 3.2% sodium citrate than with those containing EDTA 2K, and was maintained with storage at 4° C for up to 72 h after blood collection, equivalent to results with cell-stabilizing blood collection tubes. Analysis of cfDNA stored for 7 years showed that samples with low allele frequency (AF) deteriorated more readily than samples with high AF. Despite the same storage period and extraction method, AF of plasma stored for 7 years was remarkably lower than that of cfDNA. However, deterioration due to long-term plasma storage was overcome by changing the DNA extraction method from a silica membrane spin column to a cellulose magnetic beads system. These results can guide the establishment of standardized pre-analytical procedures for liquid biopsy with cfDNA.
Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. ...Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme.
The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor.
Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved.
Highlights • Endogenous DDR2 protein expression levels were high in 29% of lung SQCC patients. • A DDR2 mutation (T681I) identified in a lung SQCC clinical sample and the cell line. • Forced ...expression of DDR2 induced invasion in vitro and metastasis in animal model. • Ectopic expression of DDR2 induced MMP1 mRNA expression. • T681I mutation seems to be an inactivating mutation.
Detection of epidermal growth factor receptor (EGFR) mutations is indispensable to determine an appropriate lung cancer treatment. Although retreatment often prolongs survival, how to select the ...appropriate population for retreatment has not been clarified.
We used novel methods to identify EGFR mutations: wild inhibiting polymerase chain reaction (PCR) and quenched probe system (WIP-QP) for exon 19 deletions and mutation-biased PCR and quenched probe system for L858R. After the detection limits were determined, we examined DNA isolated from lung cancer specimens and circulating plasma DNA samples of 39 adenocarcinoma patients whose primary tumors harbored EGFR exon 19 deletions or L858R.
Detection limit was 0.005 to 0.04 ng in genomic DNA and 0.1% to 0.3% in mutant plasmids. The results of cancer tissue specimens were identical to those with existing systems (nucleic acid-locked nucleic acid PCR clamp or cycleave PCR), except for two samples that showed both exon 19 deletions and L858R. One of the two samples was confirmed to harbor L858R mutation by allele-specific oligonucleotide PCR; the other one did not. Exon 19 deletions and L858R were detected in 44.7% and 8.7% of patients, using plasma DNA, among those who carried the identical abnormalities in primary tumors all of cases that evidenced pathological stage IV except for one patient, suggesting that EGFR mutations might be preferentially detected in plasma DNA obtained from patients in advanced stages. Serial monitoring of these mutations with T790M, a gate keeper mutation, demonstrated correlation with disease state.
Our novel detection systems for EGFR mutations could be useful not only at the beginning of treatment but also for monitoring using plasma DNA for deciding appropriate treatment, including rechallenge with EGFR-tyrosine kinase inhibitors.
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