Guidance on the use of canakinumab in patients with cryopyrin-associated periodic syndrome in Japan

Cryopyrin-associated periodic syndrome (CAPS) is an orphan disease with incidence of about one in 1,000,000 persons. This autoinflammatory disease develops in the neonatal period or early childhood, with various inflammatory symptoms occurring repeatedly throughout the patient’s lifetime. It is caused by abnormality of the NLRP3 protein which mediates the intracellular signal transduction mechanism of inflammatory processes, resulting in continuous overproduction of interleukin (IL)-1β, which induces chronic inflammation and progressive tissue damage. Definitive diagnosis of CAPS is difficult, and treatment has also been difficult because of a lack of effective medications in Japan. Clinical studies of human anti-human IL-1β monoclonal antibody (canakinumab) treatment were conducted in Japan, and approval was granted for therapeutic use of canakinumab for CAPS in September 2011. Similar to other biological drugs, canakinumab is clinically highly effective. However, sufficient attention to the method of use and adverse drug reactions is necessary. This guidance describes the use of canakinumab in Japan for CAPS in relation to exclusion criteria, method of use, evaluation criteria, and adverse drug reactions.     

Successful esophageal bypass surgery in a patient with a large tracheoesophageal fistula following endotracheal stenting and chemoradiotherapy for advanced esophageal cancer: case report

A 63-year-old man with esophageal achalasia for more than 20 years complained of respiratory distress. He was admitted as an emergency to the referral hospital three months previously. Computed tomography revealed tracheobronchial stenosis due to advanced esophageal cancer with tracheal invasion. He underwent tracheobronchial stenting and chemoradiotherapy. A large tracheoesophageal fistula (TEF) developed after irradiation (18 Gy) and chemotherapy, and he was unable to eat. Thereafter, he was referred to our hospital, where we performed esophageal bypass surgery using a gastric conduit. A percutaneous cardiopulmonary support system was prepared due to the risk of airway obstruction during anesthesia. A small-diameter tracheal tube inserted into the stent achieved ordinary respiratory management. No anesthesia-related problems were encountered. Oral intake commenced on postoperative day 9. He was discharged on postoperative day 23 and was able to take in sustenance orally right up to the last moment of his life. Esophageal bypass under general anesthesia can be performed in patients with large TEF with sufficient preparation for anesthetic management.     

Improvement of blood compatibility on polysulfone-polyvinylpyrrolidone blend films as a model membrane of dialyzer by physical adsorption of recombinant soluble human thrombomodulin (ART-123)

ART-123 is a recombinant soluble human thrombomodulin (hTM) with potent anticoagulant activity, and is available for developing antithrombogenic surfaces by immobilization. We focused on improving blood compatibility on the dialyzer surface by the physical adsorption of ART-123 as a safe yet simple method without using chemical reagents. The physical adsorption mechanism and anticoagulant activities of adsorbed hTM on the surface of a polysulfone (PSF) membrane containing polyvinylpyrrolidone (PVP) as a model dialyzer were investigated in detail. The PVP content of the PSF-PVP films was saturated at 20 wt% after immersion in Tris-HCl buffer, even with the addition of over 20 wt% PVP. The surface morphology of the PSF-PVP films was strongly influenced by the PVP content, because PVP covered the outermost surface of the PSF-PVP films. The adsorption speed of hTM slowed dramatically with increasing PVP content up to 10 wt%, but the maximum adsorption amount of hTM onto the PSF-PVP film surface was almost the same, regardless of the PVP content. The PSF-PVP film with the physically adsorbed hTM showed higher protein C activity as compared to the PSF film, it showed excellent blood compatibility due to the protein C activity and the inhibition properties of platelet adhesion. The physical adsorption of hTM can be useful as a safe yet simple method to improve the blood compatibility of a dialyzer surface.     

Granulocytic sarcoma of the colon in chronic myelomonocytic leukemia

A 59-year-old man with a six-month history of chronic myelomonocytic leukemia (CMML) was admitted to the Kitasato University Hospital because of melena in September 2000. Colonofiberscopy and barium enema demonstrated an ulcerated tumorous lesion in the transverse colon. The histopathologic findings of the ulcer bed revealed diffuse infiltration of granulocytes at each stage of differentiation. The diagnosis of granulocytic sarcoma (GS) was made. Surgical resection was not indicated, because thrombocytopenia was hardly improved enough to allow surgery despite repetitive transfusion of platelet concentrates. CMML developed to refractory anemia with excess of blast in transformation in February 2001. Two courses of low dose cytarabine plus aclarubicin were ineffective on the GS in spite of a decrease in the peripheral blood blasts. Progression to acute myeloid leukemia eventually broke out, in July 2001. The patient died of leukemia complicated with pneumonia and intestinal obstruction. At present, nine cases of GS in the colon have been reported. However, these cases did not include CMML. This is the first report describing GS in the colon associated with CMML.     

Atherosclerosis is accelerated in patients with long-term well-controlled systemic lupus erythematosus (SLE)

BACKGROUND: It is uncertain whether atherosclerosis is accelerated in premenopausal and postmenopausal patients with long-term well-controlled systemic lupus erythematosus (SLE). METHODS: We measured the intima-media thickness (IMT) of the carotid arteries and the cardio-ankle vascular index (CAVI) in 39 women with SLE and in age- and sex-matched controls. RESULTS: In the premenopausal state, carotid plaque was detected only in SLE patients (36%). In the postmenopausal state, the maximum IMT was about 2-fold greater in SLE patients than in control subjects (1.3+/-0.7 vs. 0.7+/-0.2 mm, p<0.001). CAVI was higher in both the premenopausal and postmenopausal SLE patients. The serum amyloid A protein (SAA) was higher in SLE patients in the premenopausal state (p=0.025), while remnant like particle-cholesterol (RLP-C), the homeostasis model assessment of insulin resistance (HOMA-IR), and SAA were significantly increased in postmenopausal SLE patients (p=0.001, p<0.001 and p<0.05, respectively). Multiple regression analysis revealed that the maximum IMT was associated with cumulative PSL dosage (p=0.027) and SAA (p=0.074) in the premenopausal SLE patients, and with HOMA-IR (p<0.001) in the postmenopausal SLE patients. CONCLUSION: Atherosclerosis is accelerated in long-term well-controlled SLE. More attention should be given to subclinical inflammation and insulin resistance in the management of SLE patients.     

Correction of hyperglycaemia reduces insulin resistance and serum soluble E-selectin levels in patients with Type 2 diabetes mellitus.

AIMS: To investigate the effects of glycaemic control on insulin sensitivity and serum concentrations of soluble vascular cell adhesion molecule (sVCAM)-1 and E-selectin (sE-selectin) in patients with Type 2 diabetes mellitus. To examine whether reductions in serum adhesion molecule levels correlate with improvement in insulin resistance. METHODS: A total of 54 patients with Type 2 diabetes were treated for 4 weeks with either diet alone, sulphonylurea or insulin. Fasting glucose, insulin sensitivity, lipids, sVCAM-1, and sE-selectin levels were measured before and after treatment. RESULTS: All treatment modalities successfully corrected hyperglycemia. Reductions in blood glucose levels resulted in improvement in insulin sensitivity (diet KITT 2.40 +/- 0.26-3.09 +/- 0.36, P < 0.01; sulphonylurea 2.24 +/- 0.16-2.94 +/- 0.18, P < 0.01; insulin 1.68 +/- 0.27-2.16 +/- 0.22%/min, P < 0.05), and decrease in sE-selectin levels (diet 88.4 +/- 14.9-66.2 +/- 10.8, P < 0.05; sulphonylurea 85.1 +/- 11.6-59.8 +/- 7.8, P < 0.01; insulin 84.4 +/- 8.7-66.8 +/- 7.4 ng/ml, P < 0.01), but no change in sVCAM-1 levels. There was a significant correlation between the degree of decrease in sE-selectin levels and improvement in insulin sensitivity (r = -0.38, P < 0.01). CONCLUSIONS: Correction of hyperglycaemia, independent of treatment modality, resulted in improvement of insulin resistance and decrease in sE-selectin levels. These changes might, in part, contribute to reduce the risk of diabetic microvascular and macrovascular complications in patients with Type 2 diabetes mellitus.     

Assessment of neoadjuvant chemotherapy for patients with advanced squamous cell carcinoma of the esophagus

Background  Neoadjuvant chemotherapy for advanced esophageal cancer is beneficial for responders, whereas it may provide no clinical benefits or even prove harmful in non-responders. Methods  This study retrospectively compared the pathological findings and prognosis of 60 patients with UICC non-T4 stage III and IV, who received chemotherapy followed by surgery, and 96 patients with non-T4 stage III and IV cancer, who underwent surgery alone. The treatment regimen of cisplatin (70 mg/m²/day on day 1), adriamycin (30 mg/m²/day on day 1), and 5-fluorouracil (750 mg/m²/day on days 1–7) was administered for two cycles. Responders represented patients with histological effect of grade 1b-3 following therapy; non-responders represented those with grade 0-1a histological effect. Results  Survival was not significantly different between the neoadjuvant chemotherapy group and the surgery-alone group. Responders showed a tendency of earlier postoperative pStages than preoperative cStages (P = 0.08), better survival (P = 0.10), significantly fewer metastatic nodes, and significantly less extensive lymphatic invasion than the surgery-alone group. However, non-responders showed no significant differences in the degree of downstaging, number of metastatic nodes, extent of lymphatic and venous invasion, and survival rate as compared with the surgery-alone group. Comparison of overall survival between the chemotherapy and surgery-alone groups after matching for pathological stage showed that the survival of pStage II patients of the chemotherapy group was significantly better than the pStage II patients of the surgery-alone group (P = 0.04), whereas that of pStage III and IV patients of the chemotherapy group was not significantly different from the same-stage patients of the surgery-alone group. Conclusions  These results suggest that chemotherapy improves prognosis of responders significantly more than those who show downstaged pathological stage. However, the chemotherapy does not give any clinical benefit for non-responders.