SWI by 7T MR Imaging for the Microscopic Imaging Diagnosis of Astrocytic and Oligodendroglial Tumors.

BACKGROUND AND PURPOSE: Despite advances in molecular imaging, preoperative diagnosis of astrocytomas and oligodendrogliomas can be challenging. In the present study, we assessed whether 7T SWI can be used to distinguish astrocytomas and oligodendrogliomas and whether malignant grading of gliomas is possible. MATERIALS AND METHODS: 7T SWI was performed on 21 patients with gliomas before surgery with optimization for sharp visualization of the corticomedullary junction. Scoring for cortical thickening and displacement of medullary vessels, characteristic of oligodendroglial tumors, and cortical tapering, characteristic of astrocytic tumors, was performed. Additionally, characteristics of malignancy, including thickening of the medullary veins, the presence of microbleeds, and/or necrosis were scored. RESULTS: Scoring for oligodendroglial (highest possible score, +3) and astrocytic (lowest score possible, -3) characteristics yielded a significant difference between astrocytomas and oligodendrogliomas (mean, -1.93 versus +1.71, P < .01). Scoring for malignancy was significantly different among the World Health Organization grade II (n = 10), grade III (n = 4), and grade IV (n = 7) tumors (mean, 0.20 versus 1.38 versus 2.79). Cortical thickening was observed significantly more frequently in oligodendrogliomas (P < .02), with a sensitivity of 71.4% and specificity of 85.7%; observation of tapering of the cortex was higher in astrocytomas (P < .01) with a sensitivity of 85.7% and specificity of 100%. CONCLUSIONS: Visualization of the corticomedullary junction by 7T SWI was useful in distinguishing astrocytomas and oligodendrogliomas. Observation of tapering of the cortex was most sensitive and specific for diagnosing astrocytomas. Reliably predicting malignant grade was also possible by 7T SWI.

Stereotactic radiotherapy for hepatocellular carcinoma induced by hepatitis C and the relationships of changes in carbohydrate antigen 19-9 with AFP and PIVKA-II.

PURPOSE: Assessing the therapeutic effects of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) takes time. Purpose of our study was to explore the relationships of changes in carbohydrate antigen 19-9 (CA 19-9) with those in the existing markers alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II). PATIENTS AND METHODS: The subjects were 16 patients who underwent SBRT for solitary HCC ≤3cm induced by hepatitis C between June 2016 and July 2019. Observation periods ranged from 8-43 (median: 28) months, ages from 59-85 (median: 65) years. RESULTS: Changes in CA 19-9 levels after SBRT were categorised into three patterns: 1) a transient elevation followed by a decline (75%); 2) a transient decline followed by an elevation (18.8%); and 3) no change (6.3%). Among patients showing a transient CA 19-9 elevation followed by a decline, which was the most frequent pattern, 75% showed these changes in synchronisation with AFP and preceded the changes in PIVKA-II, while in the other 25%, CA 19-9 changes were in synchronisation with PIVKA-II and preceded those in AFP. At the time of recurrence, 62.5% showed a continuous CA 19-9 elevation, either in synchronisation with other markers or by itself. CONCLUSIONS: This is the first investigation of changes in CA 19-9 levels after SBRT for HCC induced by hepatitis C. Characteristic changes in CA 19-9, AFP, and PIVKA-II levels were observed as responses after treatment. As for its correlations with tumour markers, the acute responses of PIVKA-II tended to be slower than those of CA 19-9 and AFP. Although the sample size was small, our findings raise the possibility that measuring these 3 biomarkers after SBRT may be useful for monitoring patients for HCC recurrence.

Clinical Outcomes of Post-exposure Prophylaxis following Occupational Exposure to Human Immunodeficiency Virus at Dental Departments of Hiroshima University Hospital.

BACKGROUND: Dental professionals have so many opportunities to use injection needles and sharp instruments during dental treatment that they face an increased risk of needlestick injuries. This retrospective study reports the utilization and clinical outcomes of occupational post-exposure prophylaxis (PEP) with anti-retroviral agents after being potentially exposed to HIV at the dental departments of Hiroshima University Hospital. OBJECTIVE: This study reports the utilization and clinical outcomes of occupational post-exposure prophylaxis (PEP) with antiretroviral agents after being potentially exposed to HIV at dental departments of Hiroshima University Hospital. METHODS: Data on the clinical status of HIV-infected source patients and information on HIV-exposed dental professionals from 2007 to 2018 were collected. RESULTS: Five dentists with an average experience of 5.6 years (1-15 years) were exposed. The averaged CD4-positive cell number and HIV-RNA load were 1176 (768-1898) /µl and less than 20 copies/ml, respectively, in all the patients. Two of the five HIV exposed dentists received PEP. Three months after the exposures, all of their results were negative in HIV antibody/antigen tests. CONCLUSION: ; These data might support the concept of "undetectable equals untransmittable", although HIV exposure in this study was not through sexual transmission.

Association between clinical specialty setting and disease management in patients with psoriatic arthritis: results from LOOP, a cross-sectional, multi-country, observational study.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic and debilitating disease that can be managed by different clinical specialists. OBJECTIVES: The objective of the LOOP study was to evaluate the impact of clinical specialty setting on the time to diagnosis and treatment of patients with PsA. Clinical disease activity and disease burden were also compared between clinical settings. METHODS: LOOP was a cross-sectional, multicentre, observational study conducted in 17 countries in Western and Eastern Europe, the Middle East, Latin America and Asia. Adult patients (≥18 years) with a suspected or established diagnosis of PsA who were routinely visiting a rheumatologist, dermatologist or non-rheumatology/non-dermatology physician were enrolled. All patients were assessed by both a rheumatologist and a dermatologist. RESULTS: Of 1483 enrolled patients, a total of 1273 had a confirmed diagnosis of PsA. There was no significant difference in the median time from onset of inflammatory musculoskeletal symptoms to PsA diagnosis between patients enrolled by rheumatologists and dermatologists (6.0 vs. 3.9 months). However, the median time from diagnosis to first treatment with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) was significantly shorter in the rheumatology setting compared with the dermatology setting (0 vs. 2.0 months; P < 0.001). In addition, disease activity was significantly higher in the dermatology setting compared with the rheumatology setting. CONCLUSIONS: Differences in the management and clinical status of patients with PsA were observed between the rheumatology and dermatology settings. Importantly, median time from diagnosis to first csDMARD was significantly shorter in the rheumatology setting, and patients in the dermatology setting had higher disease activity. These data show the importance of improved collaboration between rheumatologists and dermatologists.

Laparoscopic inguinal hernioplasty after robot-assisted laparoscopic radical prostatectomy.

PURPOSE: To evaluate the efficacy and safety of laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair in patients who have undergone robot-assisted laparoscopic radical prostatectomy (RALP). METHODS: From July 2014 to December 2016, TAPP inguinal hernia repair was conducted in 40 consecutive patients who had previously undergone RALP. Their data were retrospectively analyzed as an uncontrolled case series. RESULTS: The mean operation time in patients who had previously undergone RALP was 99.5 ± 38.0 min. The intraoperative blood loss volume was small, and the duration of hospitalization was 2.0 ± 0.5 days. No intraoperative complications or major postoperative complications occurred. During the average 11.2-month follow-up period, no patients who had previously undergone prostatectomy developed recurrence. CONCLUSIONS: Laparoscopic TAPP inguinal hernia repair after RALP was safe and effective. TAPP inguinal hernia repair may be a valuable alternative to open hernioplasty.

Efficacy of Eculizumab Therapy for Atypical Hemolytic Uremic Syndrome Recurrence and Antibody-Mediated Rejection Progress After Renal Transplantation With Preformed Donor-Specific Antibodies: Case Report.

Atypical hemolytic uremic syndrome (aHUS) develops as the result of unregulated complement progression and precipitates de novo thrombotic microangiopathy. Plasma therapy is used to control the progression of the complement cascade, but that therapy is not effective in all patients and is accompanied by risk of infection and/or allergy. Eculizumab has been reported as an efficient therapy for aHUS. We report the case of a 35-year old woman who underwent effective eculizumab therapy for aHUS recurrence and antibody-mediated rejection (AMR) progress after renal transplantation with preformed donor-specific antibodies (DSA). She developed end-stage renal disease due to suspicious IgA nephropathy at age 33 years. Kidney transplantation was performed at age 35 years, and aHUS recurred 2 weeks later, leading to the progressive hemolytic anemia and renal dysfunction. Therefore, she underwent plasma therapy several times. Because it was difficult to continue to plasma therapy for severe allergy, eculizumab was proposed as an alternate therapy. Treatment with eculizumab was initiated 36 days after renal transplantation. After 3 years of eculizumab treatment, and without plasma therapy, schistocytes decreased, haptoglobin increased to within normal limits, creatinine levels stabilized, and no further episodes of diarrhea were reported. At protocol biopsy 1 year after transplantation, she was diagnosed with C4d-negative subclinical AMR. However, her pathologic findings at follow-up biopsy 3 years after transplantation were recovered. We conclude that eculizumab alone, without plasma therapy, is sufficient to treat recurrence of aHUS and AMR due to DSA after renal transplantation and to maintain long-term graft function.

Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib.

Dasatinib treatment markedly increases the number of large granular lymphocytes (LGLs) in a proportion of Ph+ leukemia patients, which associates with a better prognosis. The lymphocytosis is predominantly observed in cytomegalovirus (CMV)-seropositive patients, yet detectable CMV reactivation exists only in a small fraction of patients. Thus, etiology of the lymphocytosis still remains unclear. Here, we identified NK cells as the dominant LGLs expanding in dasatinib-treated patients, and applied principal component analysis (PCA) to an extensive panel of NK cell markers to explore underlying factors in NK cell activation. PCA displayed phenotypic divergence of NK cells that reflects CMV-associated differentiation and genetic differences, and the divergence was markedly augmented in CMV-seropositive dasatinib-treated patients. Notably, the CMV-associated highly differentiated status of NK cells was already observed at leukemia diagnosis, and was further enhanced after starting dasatinib in virtually all CMV-seropositive patients. Thus, the extensive characterization of NK cells by PCA strongly suggests that CMV is an essential factor in the NK cell activation, which progresses stepwise during leukemia and subsequent dasatinib treatment most likely by subclinical CMV reactivation. This study provides a rationale for the exploitation of CMV-associated NK cell activation for treatment of leukemias.

The Rho guanine nucleotide exchange factor ARHGEF5 promotes tumor malignancy via epithelial-mesenchymal transition.

Epithelial tumor cells often acquire malignant properties, such as invasion/metastasis and uncontrolled cell growth, by undergoing epithelial-mesenchymal transition (EMT). However, the mechanisms by which EMT contributes to malignant progression remain elusive. Here we show that the Rho guanine nucleotide exchange factor (GEF) ARHGEF5 promotes tumor malignancy in a manner dependent on EMT status. We previously identified ARHGEF5, a member of the Dbl family of GEFs, as a multifunctional mediator of Src-induced cell invasion and tumor growth. In the present study, ARHGEF5 was upregulated during tumor growth factor-ß-induced EMT in human epithelial MCF10A cells, and promoted cell migration by activating the Rho-ROCK pathway. ARHGEF5 was necessary for the invasive and in vivo metastatic activity of human colorectal cancer HCT116 cells. These findings underscore the crucial role of ARHGEF5 in cell migration and invasion/metastasis. An in vivo tumorigenesis assay revealed that ARHGEF5 had the potential to promote tumor growth via the phosphatidylinositol 3-kinase (PI3K) pathway. However, ARHGEF5 was not required for tumor growth in epithelial-like human colorectal cancer HCT116 and HT29 cells, whereas the growth of mesenchymal-like SW480 and SW620 cells depended on ARHGEF5. Induction of EMT by tumor necrosis factor-α or Slug in HCT116 cells resulted in the dependence of tumor growth on ARHGEF5. In these mesenchymal-like cells, Akt was activated via ARHGEF5 and its activity was required for tumor growth. Analysis of a transcriptome data set revealed that the combination of ARHGEF5 upregulation and E-cadherin downregulation or Snail upregulation was significantly correlated with poor prognosis in patients with colorectal cancers. Taken together, our findings suggest that EMT-induced ARHGEF5 activation contributes to the progression of tumor malignancy. ARHGEF5 may serve as a potential therapeutic target in a subset of malignant tumors that have undergone EMT.

High-resolution CT findings of primary lung cancer with cavitation: a comparison between adenocarcinoma and squamous cell carcinoma.

AIM: To evaluate the high-resolution computed tomography (CT) findings of primary lung cancer with cavitation and compare the findings in adenocarcinoma and squamous cell carcinoma. MATERIALS AND METHODS: The high-resolution CT findings of tumours with cavitation were retrospectively evaluated in 60 patients. Forty-seven of the lesions were diagnosed as adenocarcinomas; 13 were diagnosed as squamous cell carcinomas. The diameters of the tumour and cavity, the maximum thickness of the cavity wall, shape of the cavity wall, the number of cavities, and the presence of ground-glass opacity, bronchial obstruction, intratumoural bronchiectasis, emphysema, and honeycombing were evaluated. The mechanisms of cavity formation were examined according to the pathological features. RESULTS: The maximum thickness of the cavity wall was significantly greater in squamous cell carcinomas than in adenocarcinomas (p=0.002). Ground-glass opacity and intratumoural bronchiectasis were significantly more common in adenocarcinomas than in squamous cell carcinomas (p<0.001 and p=0.040, respectively). Regarding the pathological findings, intratumoural bronchiectasis with or without alveolar wall destruction contributed to a significant difference between adenocarcinoma and squamous cell carcinoma (p<0.001; odds ratio [OR], 20.35; 95% confidence interval [CI], 3.87-107.10). CONCLUSION: The cavity wall tends to be thicker in squamous cell carcinomas than in adenocarcinomas. The presence of ground-glass opacity and intratumoural bronchiectasis is strongly suggestive of adenocarcinoma.

Role of definitive chemoradiotherapy using docetaxel and 5-fluorouracil in patients with unresectable locally advanced esophageal squamous cell carcinoma: a phase II study.

Definitive chemoradiotherapy (CRT) with docetaxel (DOC) and 5-fluorouracil (5-FU) is a unique regimen for esophageal cancer. In this prospective phase II study, antitumor effect and safety of CRT using DOC and 5-FU for inoperable locally advanced esophageal cancer were evaluated. DOC 7.5 mg/m2 was infused on days 1, 8, 22, and 29. 5-FU 250 mg/m2 /day was infused continuously on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-45. Radiotherapy was given to 66 Gy in 33 fractions. Eleven patients with thoracic and five with cervical esophageal cancer were eligible. All patients had esophageal squamous cell carcinoma (ESCC). The response rate was 94%, with complete response in five patients (31%) and partial response in 10 (63%). Hematologic toxicity was mild; only one patient (6%) had Grade 1 leukopenia. Nonhematologic Grade 3 or higher adverse events were esophagitis (31%), anorexia (6%), and esophago-bronchial fistula (6%). No treatment-related deaths occurred. The median time to progression was 20 months and overall 3-year and 5-year survival were 44% and 31%, respectively. Definitive CRT using DOC and 5-FU could be performed safely, and it demonstrated a favorable antitumor effect for ESCC. This regimen might be indicated in patients in whom it is desirable to avoid myelosuppression and progression of renal impairment.

Vaspin prevents elevation of blood pressure through inhibition of peripheral vascular remodelling in spontaneously hypertensive rats.

AIM: Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a relatively novel adipocytokine with protective effects on metabolic diseases including obesity and type II diabetes. We have previously demonstrated that vaspin exerts anti-inflammatory and antimigratory roles through antioxidative effects in vascular smooth muscle cells. As inflammatory responses and migration of smooth muscle in peripheral vascular wall are key mechanisms for the pathogenesis of hypertension, we hypothesized that vaspin could prevent the development of hypertension in in vivo hypertensive animal model. METHODS: Vaspin (1 µg kg(-1)  day(-1) ) was administered intraperitoneally to 5-week-old male spontaneously hypertensive rats (SHR) for 4 weeks. Superior mesenteric artery was isolated and used for measurement of isometric contraction and histological analysis. RESULTS: Long-term vaspin treatment significantly prevented an elevation of systolic blood pressure (SBP) at 8 weeks of age. Vaspin had no effect on reactivity of isolated mesenteric artery from SHR. In contrast, vaspin significantly inhibited mesenteric arterial wall hypertrophy in SHR. Moreover, vaspin significantly inhibited an increase of tumour necrosis factor-α expression and a production of reactive oxygen species in isolated mesenteric artery from SHR. CONCLUSION: This study for the first time demonstrates that vaspin prevents the increase of SBP in SHR through inhibiting peripheral vascular hypertrophy possibly via antioxidative and anti-inflammatory mechanisms.

Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression.

c-Src is upregulated in various human cancers, suggesting its role in malignant progression. However, the molecular circuits of c-Src oncogenic signaling remain elusive. Here we show that Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression. Previously, we showed that transformation of fibroblasts is promoted by the relocation of c-Src to non-raft membranes. In this study, we identified Fer and ezrin as non-raft c-Src targets. c-Src directly activated Fer by initiating its autophosphorylation, which was further amplified by Fer oligomerization. Fer interacted with active c-Src at focal adhesion membranes and activated Fer-phosphorylated ezrin to induce cell transformation. Fer was also crucial for cell transformation induced by v-Src or epidermal growth-factor receptor activation. Furthermore, Fer activation was required for tumorigenesis and invasiveness in some cancer cells in which c-Src is upregulated. We propose that the Src-Fer axis represents a new therapeutic target for treatment of a subset of human cancers.

Expression of anti-Porphyromonas gingivalis peptidylarginine deiminase immunoglobulin G and peptidylarginine deiminase-4 in patients with rheumatoid arthritis and periodontitis.

BACKGROUND AND OBJECTIVE: Autoimmunity against citrullinated proteins through peptidylarginine deiminase (PAD) may be involved in the pathophysiology of rheumatoid arthritis (RA). The present study evaluated the serum levels of antibodies to citrullinated proteins and to Porphyromonas gingivalis PAD (PPAD), and the endogenous expression of PAD-4, in individuals with and without RA, as well as before and after periodontal treatment. MATERIAL AND METHODS: The study participants consisted of 52 patients with RA (RA group) and 26 age-, gender- and smoking status-matched healthy controls (non-RA group). Of the 52 patients, 26 were randomly assigned to receive oral hygiene instruction and supragingival scaling (RA subgroup). After periodontal and rheumatologic assessments, the serum levels of anti-cyclic citrullinated peptide (CCP) immunoglobulin G (IgG), anti-PPAD IgG and PAD-4 were determined using ELISA. RESULTS: The serum levels of anti-CCP IgG and anti-PPAD IgG were significantly higher in the RA group than in the non-RA group (p < 0.001 and p = 0.03). A significant, positive correlation was observed between the serum levels of anti-PPAD IgG and anti-CCP IgG (p = 0.04), but not between the serum levels of PAD-4 and anti-CCP IgG. Multiple logistic regression analyses revealed a significant association between anti-PPAD IgG responses and RA after adjustment for age, gender and smoking (p = 0.004). Supragingival scaling significantly improved the periodontal condition and disease activity of RA (p < 0.05), but failed to decrease the serum levels of anti-CCP IgG, anti-PPAD IgG and PAD-4 after 2 mo of treatment. CONCLUSION: These results might suggest an association between anti-PPAD IgG and anti-CCP IgG responses, implicating a role for PPAD in protein citrullination in patients with RA and periodontitis.

Effect of γ-cyclodextrin as a lyoprotectant for freeze-dried actinidin.

Actinidin (ATD) is a cysteine protease found in kiwifruit. It is used to tenderize meat and to enhance the digestion of proteins in the small intestine. However, ATD is unstable during freeze-drying, which alters its bioactivity. It is well known that sugars have the ability to protect proteins from the stress of freeze-drying. In this study, we investigated the protective effect of various saccharides on the stability of ATD during freeze-drying. The ATD activities of the samples containing γ-cyclodextrin (CyD) showed only a small decrease, and compared with trehalose and sucrose, γ-CyD was a more effective stabilizer for ATD. Secondary structural changes in freeze-dried ATD were observed by circular dichroism spectroscopy and compared with the changes in stabilized samples. There was a close relationship between the α-helix content and the stabilization. The sugars stabilized the protein by suppressing the changes in the α-helix. Fourier transform infrared spectroscopy measurement showed that the amide I band of ATD with γ-CyD was shifted to a lower wavenumber compared with other sugars. Therefore, stronger hydrogen bonds may be formed between ATD and γ-CyD than between ATD and other sugars. The suppression of changes in the protein secondary structure accompanying the formation of hydrogen bonding between the protein and the sugar also contributed to the protective effect of the sugars.

Effects of neoadjuvant chemoradiotherapy on postoperative morbidity and mortality associated with esophageal cancer.

We compared the surgical outcomes between 114 patients who did not receive neoadjuvant therapy (group 1) and 92 others who received neoadjuvant chemoradiotherapy (nCRT) (group 2), and assessed the preoperative and surgical factors that influence postoperative morbidity to determine the impact of nCRT on morbidity and mortality after esophagectomy via cervical, right transthoracic, and abdominal approaches. The overall postoperative morbidity rates were 44.7% and 55.4% in groups 1 and 2, respectively (P = 0.13). Rates of anastomotic leak (8.8% vs. 16.3%; P = 0.10), pneumonia (9.6% vs. 13.0%; P = 0.44), recurrent nerve palsy (15.8% vs. 10.9%; P = 0.31), and all other complications did not significantly differ between the groups. Multivariable analysis revealed cervical lymph node dissection (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.01-3.84; P = 0.047) as the sole independent covariate for overall morbidity. Furthermore, a history of cardiovascular disease (OR, 2.90; 95% CI, 1.03-8.24; P = 0.045), the retrosternal reconstruction route (OR, 15.15; 95% CI, 3.56-62.50; P = 0.0002), and a longer surgical duration (OR, 1.01; 95% CI, 1.002-1.02; P = 0.01) were independent covariates for anastomotic leakage, and advanced age (OR, 1.08; 95% CI, 1.01-1.15; P = 0.02) and lower body mass index (OR, 1.16; 95% CI, 1.01-1.33; P = 0.04) were independent covariates for pneumonia. However, whether or not patients received nCRT was irrelevant. We found that nCRT is safe for three-incision esophagectomy and it does not increase the incidence of postoperative morbidity and mortality relative to esophagectomy alone.

Brain-derived neurotrophic factor promotes angiogenic tube formation through generation of oxidative stress in human vascular endothelial cells.

AIM: Brain-derived neurotrophic factor (BDNF), a major type of neurotrophins, plays a role in the regulation of synaptic function. Recent studies suggest that BDNF promotes angiogenesis through its specific receptor, tropomyosin-related kinase B (TrkB). However, the detailed mechanisms for this still remain to be determined. Reactive oxygen species (ROS) generation contributes to the regulation of angiogenesis. Thus, we investigated the mechanisms by which BDNF regulates angiogenesis with focusing on ROS in cultured human vascular endothelial cells (ECs). METHODS AND RESULTS: In human umbilical vein ECs, BDNF increased ROS generation as measured fluorometrically using 2' 7'-dichlorofluorescein diacetate as well as NADPH oxidase (NOX) activity as measured by lucigenin assay. BDNF-induced ROS generation and NOX activity were inhibited by K252a, a TrkB receptor inhibitor. BDNF induced phosphorylation of p47 phox, a regulatory component of NOX, which was inhibited by K252a as measured by Western blotting. BDNF increased angiogenic tube formation in ECs, which was completely inhibited by K252a or gp91ds-tat, a NOX inhibitor. BDNF caused Akt phosphorylation in ECs, which was inhibited by K252a or gp91ds-tat. CONCLUSION: The present results for the first time demonstrate that BDNF induces NOX-derived ROS generation through activation of p47 phox in a TrkB receptor-dependent manner, which leads to the promotion of angiogenic tube formation possibly via Akt activation.