A pathological complete response after nivolumab plus ipilimumab therapy for DNA mismatch repair-deficient/microsatellite instability-high metastatic colon cancer: A case report.

The standard treatment for colorectal cancer has always been surgery and chemotherapy, which may be used in combination to treat patients. Immune checkpoint inhibitors have been a significant advancement in the standard treatment of metastatic, unresectable colorectal cancer with deficient mismatch repair. However, little information is available about their use in neoadjuvant and conversion settings with only a few case reports and only one phase 2 trial. The present study reports the case of a large, locally advanced right-sided metastatic deficient mismatch repair/microsatellite instability-high colon cancer, which showed a pathological complete response after combination treatment with nivolumab and ipilimumab. To the best of our knowledge, resected metastatic colon cancer with a pathological complete response after treatment using dual immune checkpoint inhibitors has not been previously reported. Overall, this case report suggests the use of immune checkpoint inhibitors before colorectal surgery.

4-Cl-edaravone and (E)-2-chloro-3-[(E)-phenyldiazenyl]-2-butenoic acid are the specific reaction products of edaravone with hypochlorite.

3-Methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is a synthetic one-electron antioxidant used as a drug for treatment against acute phase cerebral infarction in Japan. This drug also reacts with two-electron oxidants like peroxynitrite to give predominantly 4-nitrosoedaravone but no one-electron oxidation products. It is believed that this plays a significant role in amelioration of amyotrophic lateral sclerosis. The drug was approved for treatment of amyotrophic lateral sclerosis in Japan and USA in 2015 and 2017, respectively. In this study, we examined the reaction of edaravone with another two-electron oxidant, hypochlorite anion (ClO-). Edaravone reacted with ClO- in 50% methanolic phosphate buffer (pH 7.4) solution containing typical two-electron reductants, such as glutathione, cysteine, methionine, and uric acid, as internal references. The concentration of edaravone decreased at a similar rate as each co-existing reference, indicating that it showed comparable reactivity toward ClO- as those references. Furthermore, 4-Cl-edaravone and (E)-2-chloro-3-[(E)-phenyldiazenyl]-2-butenoic acid (CPB) were identified as primary and end products, respectively, and no one-electron oxidation products were detected. These results suggest that edaravone treatment can bring greater benefit against ClO--related injury such as inflammation, and 4-Cl-edaravone and CPB can be good biomarkers for ClO--induced oxidative stress.

Choice of the most appropriate biological disease-modifying anti-rheumatic drug for injection spacing: results from a multicentre observational study.

OBJECTIVES: To determine which biological disease-modifying anti-rheumatic drug (bDMARD) is most appropriate for spacing in patients with rheumatoid arthritis (RA) who have persistent stable symptoms. METHODS: In patients with sustained low disease activity (LDA) or better for ≥3 months who were treated with bDMARDs, the interval between bDMARD injections was extended 1.5 times, and treatment continuation rates at 104 weeks were calculated for each drug. Patients who discontinued therapy owing to adverse reactions and those who withdrew for reasons unrelated to the drugs were excluded. Whether patients could remain in LDA or better after injection spacing was investigated. The targeted drugs were an anti-tumour necrosis factor (TNF) inhibitor (golimumab [GOL]) and 2 non-TNF inhibitors (tocilizumab [TCZ] and abatacept [ABT]). RESULTS: The spacing evaluation included 57, 93, and 40 patients who received GOL subcutaneous injection (SC), TCZ (SC in 21 and drip intravenous injection [DIV] in 72), and ABT (SC in 12 and DIV in 22), respectively. At 104 weeks, the number of patients who discontinued therapy owing to adverse reactions did not significantly differ among the drugs. At 104 weeks, the treatment continuation rate was 0.71 for TCZ SC, 0.70 for GOL, 0.69 for TCZ DIV, 0.55 for ABT SC, and 0.50 for ABT DIV. The continuation rate for ABT was significantly lower than those for GOL and TCZ. No significant difference in continuation rates was observed between SC and DIV. CONCLUSIONS: When the injection interval was extended, GOL and TCZ were superior to ABT in terms of continuation rate.

Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor-α inhibitor.

OBJECT: Although cerebral aneurysmal subarachnoid hemorrhage is a devastating disease for humans, effective medical treatments have not yet been established. Recent reports have shown that regression of some inflammatory-related mediators has protective effects in experimental cerebral aneurysm models. This study corroborated the effectiveness of tumor necrosis factor-α (TNF-α) inhibitor for experimentally induced cerebral aneurysms in rats. METHODS: Five-week-old male rats were prepared for induction of cerebral aneurysms and divided into 3 groups, 2 groups administered different concentrations of a TNF-α inhibitor (etanercept), and 1 control group. One month after aneurysm induction, 7-T MRI was performed. The TNF-α inhibitor groups received subcutaneous injection of 25 µg or 2.5 µg of etanercept, and the control group received subcutaneous injection of normal saline every week. The TNF-α inhibitor administrations were started at 1 month after aneurysm induction to evaluate its suppressive effects on preexisting cerebral aneurysms. Arterial circles of Willis were obtained and evaluated 3 months after aneurysm induction. RESULTS: Rats administered a TNF-α inhibitor experienced significant increases in media thickness and reductions in aneurysmal size compared with the control group. Immunohistochemical staining showed that treatment with a TNF-α inhibitor suppressed matrix metalloproteinase (MMP)-9 and inducible nitric oxide synthase (iNOS) expression through the luminal surface of the endothelial cell layer, the media and the adventitia at the site of aneurysmal formation, and the anterior cerebral artery-olfactory artery bifurcation. Quantitative polymerase chain reaction also showed suppression of MMP-9 and iNOS by TNF-α inhibitor administration. CONCLUSIONS: Therapeutic administration of a TNF-α inhibitor significantly reduced the formation of aneurysms in rats. These data also suggest that TNF-α suppression reduced some inflammatory-related mediators that are in the downstream pathway of nuclear factor-κB.

Statin use and risk of cerebral aneurysm rupture: a hospital-based case-control study in Japan.

BACKGROUND: Recent reports have showed that some statins have protective effects in experimental cerebral aneurysm models. We conducted a case-control study to investigate an association between statin use and the rupture risk of cerebral aneurysm in Japanese population. METHODS: This was a multihospital case-control study; cases and controls were collected from 15 hospitals in Japan. Cases consisted of patients with aneurysmal subarachnoid hemorrhage hospitalized from April 2009 to March 2011. Controls were selected from patients who had newly diagnosed unruptured saccular aneurysms from April 2006 to March 2011. The primary exposure of interest was statin use. Multivariable logistic regression was used to assess the relationship between stain use and the rupture risk of cerebral aneurysm. RESULTS: A total of 117 cases and 304 controls were included in the analyses. Statin was used in 9.4% of cases and 26.0% of controls. Controls had a significantly higher rate of use of statin. The use of any statin was associated with cerebral aneurysm rupture after adjustment of potential confounders (adjusted odds ratio: .30, 95% confidence interval: .14-.66). The association was similar in each stratum of total cholesterol level. CONCLUSIONS: This observation from a hospital-based case-control study in Japan suggested that there is inverse relationship between use of statins and cerebral aneurysm rupture. Future clinical studies are needed.

Gender-related differences in target organ damage in untreated patients with essential hypertension.

We examined the gender-related differences in target organ damage in 220 untreated patients with essential hypertension (106 men and 114 women). As the indices of target organ damage, we examined the left ventricular mass index and the intima-media thickness in the carotid and femoral arteries obtained from echocardiography. In a multiple regression model, there was a significant positive correlation between the intima-media thickness and age in both groups. In men, there was a significant positive correlation between the left ventricular mass index and age, as well as the diastolic blood pressure, and body mass index. In women, there was a significant positive correlation between the left ventricular mass index and age, as well as plasma renin activity and smoking. In conclusion, there are gender-related differences in the contributing factors, which relate to left ventricular hypertrophy in patients with essential hypertension.

Prognostic significance of the number of leads with ST depression during an anginal attack in high risk patients with unstable angina.

OBJECTIVE AND METHODS: We examined the prognostic significance of electrocardiographic predictors (number of leads with ST depression, maximal ST depression, QT dispersion), C-reactive protein, fibrinogen, myosin light chain 1 and creatine kinase MB fraction in 62 patients with unstable angina showing ST depression during an anginal attack. RESULTS: During the 90-day follow-up period, 15 patients (24%) exhibited new cardiac events (death, myocardial infarction or urgent revascularization). Using multivariate analysis, the number of leads with ST depression [relative risk 6.305 (95% confidence intervals 1.831-21.71), p<0.01] during an anginal attack was found to be an independent risk factor to predict cardiac events. Other predictors did not have prognostic significance. CONCLUSION: The number of leads with ST depression during an anginal attack is an independent risk predictor for new cardiac events in high risk patients with unstable angina.

Increased plasma concentrations of intercellular adhesion molecule-1 after strenuous exercise associated with muscle damage.

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in leukocyte migration from the circulation and intervention at sites of inflammation. We investigated the effects of various types of exercise on circulating levels of soluble ICAM-1 (sICAM-1) in normal healthy male adults. Plasma concentrations of sICAM-1 were measured before and after bicycle ergometer exercise at intensity of 80% maximal oxygen consumption (VO2mag) (16 min), 42 km endurance running and 30-min downhill running at intensity of ventilation threshold (VT). The plasma sICAM-1 level increased 1 day after the endurance running (12%) and downhill running (14%), but not after ergometer exercise. Plasma C-reactive protein (CRP) and creatine kinase (CK) concentrations also increased 1 day after running. Our data suggest that exercise associated with muscle damage and/or inflammation results in increased levels of plasma sICAM-1. The physiological significance of post-exercise high plasma sICAM-1 levels is not clear at this stage, but changes in plasma sICAM-1 may reflect the status of the immune system.

Immunohistochemical detection of hepatocellular carcinoma in the setting of ongoing necrosis after radiofrequency ablation.

After radiofrequency ablation (RFA), hepatocellular carcinoma undergoes complete necrosis and an ongoing necrosis that is irreversible and characterized histologically by disrupted cell outlines, homogenous cytoplasmic eosinophilia, and preserved nuclear staining, with the cells appearing quite distinct from viable cancer cells. Antibody to detect single-stranded DNA (ssDNA) specifically labeled nuclei in the setting of ongoing necrosis, but not viable tumor cells, whereas human mitochondrial antibody labeled the cytoplasm of viable cells but not cells of ongoing necrosis. The results demonstrate that RFA causes denaturation of both DNA and proteins and that the immunohistochemistry of ssDNA and mitochondrial protein is useful in detection of ongoing necrosis after RFA and provides pathological information on the validity of this procedure.