A multicenter,open‐label,phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

Tirabrutinib is a second‐generation Bruton’s tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment‐naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström’s macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression‐free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88^L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow‐up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug‐related atrial fibrillation or hypertension. Although the follow‐up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI‐173646).     

Intracellular claudin‐1 at the invasive front of tongue squamous cell carcinoma is associated with lymph node metastasis

Claudins are the major component of tight junctions, which form a primary barrier to paracellular diffusion and maintain cell polarity in normal epithelia and endothelia. In cancer cells, claudins play additional roles besides serving as components of the tight junctions, and participate in anoikis or invasion. Among the claudin family proteins, claudin‐1 has the most promising potential, both diagnostically and prognostically, in many types of cancers, including oral, gastric, liver, and colon cancers. However, conflicting results have been reported in relation to the degree of claudin‐1 expression and the prognosis, suggesting that the expression level of claudin‐1 alone is not sufficient to analyze the relationship between claudin‐1 and cancer progression. As endocytic trafficking of claudin‐1 has been reported in several epithelial cell types in vitro, we aimed to determine whether intracellular localization of claudin‐1 is the missing aspect between claudin‐1 and cancer. We investigated the expression of claudin‐1 in 83 tongue squamous cell carcinoma (TSCC) pathological specimens. Although the expression level of claudin‐1 based on immunohistochemistry was not associated with TSCC progression, within the high claudin‐1 expression group, the incidence of intracellular localization of claudin‐1 was correlated with cervical lymph node metastasis. In an in vitro experiment, claudin‐1 was constitutively internalized in TSCC‐derived cells. Motility of TSCC‐derived cells was increased by deficiency of claudin‐1, suggesting that the decrease in cell‐surface claudin‐1 promoted the cell migration. Therefore, intracellular localization of claudin‐1 at the invasion front may represent a promising diagnostic marker of TSCC.     

Distribution of inflammatory cells in adventitia changed with advancing atherosclerosis of human coronary artery

AIM: Since atherosclerosis was recognized as an inflammatory disease in 1990, the infiltration of macrophages and T lymphocytes has been reported to be predominant in human atherosclerotic lesions. Although adventitis accompanying atherosclerosis was also described in many reports, it is still unclear whether T lymphocytes or B lymphocytes are predominant in the adventitis. In this study, the authors immunohistochemically investigated the correlation between the transition of infiltrating inflammatory cells in the adventitia with atherosclerosis and the type of coronary atherosclerosis. METHODS: Sixty-four coronary atherosclerotic lesions from a surgical specimen and 47 autopsy cases were used for immunohistochemical study of CD45RO, CD20, CD68 and others. Atherosclerosis was classified into type I, II, III, IV according to the 1995 AHA classification. RESULTS: T lymphocyte infiltration in the adventitia was predominantly recognized in about 80% (38/48) of cases, but B lymphocyte infiltration was occasionally recognized in about 20% (10/48). Among 10 cases with B lymphocyte infiltration, small lymph follicles formed in 3 cases. This inflammatory response in adventitia subsided in type III and augmented again in type IV.CONCLUSION: This result suggested that other inflammatory stimuli were induced in the adventitia in type IV coronary atherosclerosis.     

Dermatopathic Lymphadenopathy With Increased IgG4-Positive Plasma Cells

Both dermatopathic lymphadenopathy (DL) and immunoglobulin G4-related disease (IgG4-RD) are frequently complicated with allergic diseases. However, the relationship between DL and IgG4-RD is not well known. To clarify this relationship on the basis of clinical and pathological findings, including IgG4-positive (IgG4+) plasma cell infiltration in lymph nodes (LNs) of DL patients, we analyzed LNs of 11 DL patients using immunostaining of IgG, IgG4, forkhead box P3 (FOXP3), transforming growth factor (TGF)-β, interferon (IFN)-γ, and matrix metalloproteinase (MMP)-1, MMP-8, and MMP-13. Toluidine blue staining was also performed to identify mast cells. Of 3 patients with a high ratio of IgG4+/IgG+ cells (>40%) and elevated serum IgG4 levels, 2 developed IgG4-RD, whereas the other patient did not. Of 8 patients with a low ratio of IgG4+/IgG+ cells (<40%) or no infiltration of IgG4+ cells, 5 who could be followed did not develop IgG4-RD. The numbers of mast cells were similar to those of TGF-β-positive cells, and serial sections showed that mast cells possibly produce TGF-β. LNs of DL patients with a high ratio of IgG4+/IgG+ cells had significantly more mast cells and TGF-β-positive cells than those of patients with a low ratio of IgG4+/IgG+ cells or no infiltration of IgG4+ cells. However, no fibrosis was observed in LNs of both groups. IFN-γ was positive in interdigitating dendritic cells, Langerhans cells, and macrophages. MMP-1, MMP-8, or MMP-13 was expressed in macrophages. The lack of fibrosis in LNs may have been due to the production of IFN-γ, MMP-1, MMP-8, or MMP-13. Thus, DL with increased IgG4+ cells seems to be a phenotype of IgG4-RD in LNs.     

Inhibitory effects of FUT-175, a new synthetic protease inhibitor, on intravascular hemolysis by human serum in mice

Effects of FUT-175, a new protease inhibitor, on intravascular hemolysis of mouse erythrocytes caused by intravenous injection of human serum was studied in mice. In in vitro experiments, unsensitized erythrocytes obtained from various species of animals were lysed with sera in EGTA-GVB-Mg++. After heat inactivation of sera at 50 degrees C for 30 min, hemolysis in EGTA-GVB-Mg++ was abolished, indicating loss of activity of the alternative complement pathway. FUT-175 inhibited the alternative complement pathway-mediated hemolysis with IC50 values of 1.3 X 10(-7) to 4.0 X 10(-7) M. Intravenous injection of human serum caused intravascular hemolysis of mouse erythrocytes in mice. No remarkable change was observed in the mice that were injected with heat-inactivated (56 degrees C, 30 min) human serum. Intravenous administration of FUT-175 at a dose of 3 or 10 mg/kg inhibited intravascular hemolysis of mouse erythrocytes regardless of whether it was administered before or after injection of human serum. These results indicated that FUT-175 prevents intravascular hemolysis of mouse erythrocytes through the inhibitory effect of both alternative and classical complement pathway.     

Temporal prediction modulates the evaluative processing of “good” action feedback: An electrophysiological study

The present study aimed to investigate whether or not the evaluative processing of action feedback can be modulated by temporal prediction. For this purpose, we examined the effects of the predictability of the timing of action feedback on an ERP effect that indexed the evaluative processing of action feedback, that is, an ERP effect that has been interpreted as a feedback‐related negativity (FRN) elicited by “bad” action feedback or a reward positivity (RewP) elicited by “good” action feedback. In two types of experimental blocks, the participants performed a gambling task in which they chose one of two cards and received an action feedback that indicated monetary gain or loss. In fixed blocks, the time interval between the participant's choice and the onset of the action feedback was fixed at 0, 500, or 1,000 ms in separate blocks; thus, the timing of action feedback was predictable. In mixed blocks, the time interval was randomly chosen from the same three intervals with equal probability; thus, the timing was less predictable. The results showed that the FRN/RewP was smaller in mixed than fixed blocks for the 0‐ms interval trial, whereas there was no difference between the two block types for the 500‐ms and 1,000‐ms interval trials. Interestingly, the smaller FRN/RewP was due to the modulation of gain ERPs rather than loss ERPs. These results suggest that temporal prediction can modulate the evaluative processing of action feedback, and particularly good feedback, such as that which indicates monetary gain.     

Fine‐scale geographic clustering pattern of human T‐cell leukemia virus type 1 infection among blood donors in Kyushu‐Okinawa,Japan

Human T‐cell leukemia virus type I (HTLV‐1) infection is endemic in Japan, particularly clustered in the southwestern district, Kyushu‐Okinawa, which consists of eight prefectures that further consist of 274 municipalities. However, no information is available about the fine‐scale distribution of HTLV‐1 infection within Kyushu‐Okinawa. To assess the municipal‐level distribution of people with HTLV‐1 infection in Kyushu‐Okinawa, we performed a cross‐sectional study using a fine‐scale geographic information system map based on HTLV‐1 screening test results from the Japanese Red Cross database from September 2012 to February 2014. Of the 881 871 (646 914 male, 234 957 female) screened blood donors, 981 were seropositive for HTLV‐1 by confirmatory test. The seroprevalence was 0.11% (95% confidence interval [CI] 0.10%‐0.12%) for all, 0.094% (95% CI, 0.09%‐0.10%) for male, and 0.16% (95% CI, 0.14%‐0.18%) for female individuals. The sex‐ and age‐specific HTLV‐1 seroprevalence varied significantly across municipalities; particularly, the seroprevalence among women aged 50 years was significantly higher than that of men in both the mainland of Kyushu‐Okinawa and the satellite island, in all of which the seroprevalence of HTLV‐1 was more than 1.2%. These results show that, even in the Kyushu‐Okinawa district, there are endemic clusters of HTLV‐1 in small areas. This suggests that public health education programs are needed to eliminate new HTLV‐1 infection in these areas.     

Identification by proteomic analysis of calreticulin as a marker for bladder cancer and evaluation of the diagnostic accuracy of its detection in urine

BACKGROUND: New methods for detection of bladder cancer are needed because cystoscopy is both invasive and expensive and urine cytology has low sensitivity. We screened proteins as tumor markers for bladder cancer by proteomic analysis of cancerous and healthy tissues and investigated the diagnostic accuracy of one such marker in urine. METHODS: Three specimens of bladder cancer and healthy urothelium, respectively, were used for proteome differential display using narrow-pH-range two-dimensional electrophoresis. To evaluate the presence of calreticulin (CRT) as detected by Western blotting, we obtained 22 cancerous and 10 noncancerous surgical specimens from transurethral resection or radical cystectomy. To evaluate urinary CRT, we collected 70 and 181 urine samples from patients with and without bladder cancer, respectively. Anti-CRT COOH-terminus antibody was used to detect CRT in tissue and urine. RESULTS: Proteomic analysis revealed increased CRT (55 kDa; pI 4.3) in cancer tissue. Quantitative Western blot analysis showed that CRT was increased in cancer tissue (P = 0.0003). Urinary CRT had a sensitivity of 73% (95% confidence interval, 62-83%) at a specificity of 86% (80-91%) for bladder cancer in the samples tested. CONCLUSIONS: Proteomic analysis is useful in searching for candidate proteins as biomarkers and led to the identification of urinary CRT. The diagnostic accuracy of urinary CRT for bladder cancer appears comparable to that of Food and Drug Administration-cleared urinary markers, but further studies are needed to determine its diagnostic role.     

Validity of skin blot examination for albumin and nerve growth factor β to detect itching of the skin in Indonesian older adults

AimItching, a common skin disorder, impacts the quality of life of individuals. Itchy skin occurs more with increasing age and the prediction of itchy skin prognosis is necessary to provide good skincare. This study validated biomarkers in skin blotting to identify and measure itching sensation as well as conventional methods to measure skin barrier function.Materials and methodsFrom a cross-sectional study conducted in Long-term Care (LTC) facilities in Indonesia itching symptoms were obtained through a questionnaire. Skin conditions were assessed using photographs, stratum corneum (SC) hydration, skin pH, and skin blotting for biomarkers: albumin, interleukin 2 (IL2), nerve growth factor β (NGFβ), and thymic stromal lymphopoietin (TSLP). Association of skin measurements with the presence of skin blotting and trends analysis were conducted.ResultsAltogether, 564 LTC residents (average age, 70 years) participated. The SC hydration, skin pH, albumin, and NGFβ were associated with the presence of itch (p value= <0.001, <0.001, <0.001, and <0.001, respectively). The signal levels of skin blotting biomarkers were higher in itch group than in the non-itch group. Additionally, the higher quantile of SC hydration was significantly associated with a lower intensity level of NGFβ and TSLP (p value = 0.005, 0.003, respectively). The lower quantile of skin pH (better skin condition) was significantly associated with lower albumin, NGFβ, and TSLP (p value = 0.048, 0.035, and <0.001, respectively).ConclusionThe albumin, NGFβ, and TSLP could be a candidate for measurement of itchy skin among older adult with disrupted skin barrier function and local skin inflammation.     

Prefrontal cortex and amygdala volume in first minor or major depressive episode after cancer diagnosis.

BACKGROUND: Major and minor depressive episodes in cancer patients are frequent and are frequently seen as the first depressive episode in a patient's life. However, the neurological basis of these depressive episodes remains largely unknown. METHODS: Subjects were 51 breast cancer survivors (BCS) who had no history of any depressive episode before the cancer diagnosis (11 BCS with a history of a first minor depressive episode after cancer diagnosis, 11 BCS with a history of a first major depressive episode after cancer diagnosis, and 29 BCS with no history of any depressive episode after cancer diagnosis). We analyzed the prefrontal cortex (PFC) and amygdala volumes in a 1.5-Tesla Magnetic Resonance Imaging scanner. We characterized the structural correlates of depression using two complementary approaches. The first was voxel-based morphometry (VBM) that allowed us to scan the entire brain for reactive gray matter deficit. The second was classical volumetry focusing on the amygdala. RESULTS: Voxel-based morphometry revealed no brain region, including PFC, for which volume was significantly different among the three groups. There were trend-level differences in the left amygdala volume in the manual tracing method among the three groups. The left amygdala volumes in the subjects with a first minor and/or major depressive episode were significantly smaller than in those with no history of any depressive episode. CONCLUSIONS: It might be suggested that amygdala volume was associated with a first minor and/or major depressive episode after cancer diagnosis.