Case of severe alcoholic hepatitis treated with granulocytapheresis

Severe alcoholic hepatitis (AH) has a high mortality, and it is associated with encephalopathy, acute renal failure, sepsis, gastrointestinal bleeding, and endotoxemia. The 28-d mortality remains poor (34%-40%), because no effective treatment has been established. Recently, corticosteroids (CS) have been considered effective for significantly improving the prognosis of those with AH, as it prevents the production of pro-inflammatory cytokines. However, CS are not always appropriate as an initial therapeutic option, such as in cases with an infection or resistance to CS. We describe a patient with severe AH complicated by a severe infection caused by the multidrug resistance bacteria (Pseudomonas aeruginosa), and was successfully treated with granulocytapheresis monotherapy without using CS. The experience of this case will provide understanding of the disease and information treating cases without using CS.     

A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma

We conducted a phase 1/2 study of single‐agent carfilzomib in Japanese patients with relapsed/refractory multiple myeloma. Safety, pharmacokinetics and pharmacodynamics of carfilzomib were examined in phase 1. The primary endpoint in phase 2 was the overall response rate (ORR). Carfilzomib was administered in a twice‐weekly, consecutive‐day dosing schedule. In Phase 1, doses of 15 or 20 mg/m² were administered on this schedule or 20 mg/m² on Days 1 and 2 of Cycle 1 and then 27 mg/m² in the 20/27 mg/m² cohort. Patients had a median of five prior therapies, including bortezomib and an immunomodulatory agent. The dose level did not reach the maximum tolerated dose. The most common adverse events were haematological. Notably, carfilzomib either induced new hypertension (n = 4) or aggravated previously existing hypertension (n = 6) in 10 of 50 patients. Four of the eight patients who previously experienced peripheral neuropathy (PN) experienced a recurrence with carfilzomib use, but no new cases of PN occurred. The ORR of the 20/27 mg/m² 40 patient cohort was similar to that in the pivotal US study. The dose was efficacious and tolerable in heavily pre‐treated Japanese patients; however, meticulous control of hypertension may be necessary for further carfilzomib use.     

Liver-targeted hydrodynamic gene therapy: Recent advances in the technique

One of the major research focuses in the field of gene therapy is the development of clinically applicable, safe, and effective gene-delivery methods. Since the first case of human gene therapy was performed in 1990, a number of gene-delivery methods have been developed, evaluated for efficacy and safety, and modified for human application. To date, viral-vectormediated deliveries have shown effective therapeutic results. However, the risk of lethal immune response and carcinogenesis have been reported, and it is still controversial to be applied as a standard therapeutic option. On the other hand, delivery methods for nonviral vector systems have been developed, extensively studied, and utilized in in vivo gene-transfer studies. Compared to viral-vector mediated gene transfer, nonviral systems have less risk of biological reactions. However, the lower gene-transfer efficiency was a critical hurdle for applying them to human gene therapy. Among a number of nonviral vector systems, our studies focus on hydrodynamic gene delivery to utilize physical force to deliver naked DNA into the cells in the living animals. This method achieves a high gene-transfer level by DNA solution injections into the tail vein of rodents, especially in the liver. With the development of genome editing methods, in vivo gene-transfer therapy using this method is currently the focus in this research field. This review explains the method principle, efficiency, safety, and procedural modifications to achieve a high level of reproducibility in large-animal models.     

Properties of the prototype 256-row (cone beam) CT scanner

We evaluated Feldkamp artifacts, which are specific to cone-beam computed tomography (CT), in phantom and clinical studies using the 256-multidetector-row CT (256MDCT), and compared the reconstruction accuracy of axial and helical scans. Image noise, slice sensitivity profile (SSP) and artifacts with the 256MDCT were evaluated using a phantom, and the results were compared to those of a 64MDCT. We also examined chest and abdomen scans produced with the 256MDCT in volunteers. For the axial scan, Feldkamp artifacts were visualized as high-frequency streak-like artifacts that are oriented horizontally at the edge of the scan region in the phantom study. Similar results were obtained with the volunteers in soft-tissue regions near either bony structures or air pockets. Feldkamp artifacts with the 256MDCT can lead to misdiagnosis if not correctly identified and minimized via helical scanning. Image noise was less for axial than helical scans, while SSP was better with helical than axial scans. Feldkamp artifacts observed in the 256MDCT images, however, did not generally affect the interpretation of images. The 256MDCT promises more accurate diagnosis, and will provide volumetric cine images of wider cranio-caudal coverage, enabling new applications of CT.     

Postmortem cardiac troponin T levels in the blood and pericardial fluid. Part 1. Analysis with special regard to traumatic causes of death

In forensic pathology, previous studies have suggested the possible application of cardiac troponins in the diagnosis of myocardial infarction. However, there appears to be insufficient practical data on other causes of death. The present study was a comprehensive analysis of the cardiac, peripheral blood and pericardial levels of cardiac troponin T (cTnT) in serial medicolegal autopsy cases (n = 405) with a survival time <24 h and within 48 h postmortem to assess the validity of investigating myocardial damage with special regard to traumatic causes of death. These included blunt and sharp instrument injury (n = 122 and 21, respectively), asphyxiation (n = 35), drowning (n = 27), fire fatalities (n = 94), hyperthermia (n = 13), hypothermia (n = 6), fatal methamphetamine (MA) abuse (n = 12) and carbon monoxide (CO) poisoning (n = 5) in comparison with myocardial infarction (MI, n = 57) and cerebrovascular diseases (n = 13). Cases within 12h postmortem usually showed lower cardiac and pericardial cTnT levels than did those of longer postmortem time of 12-48 h. In the early postmortem period of <12 h, significantly elevated serum cTnT levels were observed for hyperthermia. Thereafter, fatal MA abuse, CO poisoning and MI cases also showed higher levels. However, cTnT remained at lower levels for hypothermia and drowning. The elevation of cTnT was associated with the pathology of advanced myocardial damage involving swelling and liquefactive necrosis. The above-mentioned differences were the smallest for peripheral blood. These findings suggest that elevations in postmortem serum and pericardial cTnT levels depend on the severity of myocardial damage at the time of death and are related to the pathological findings, although postmortem interference should be taken into consideration.     

Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours

Purpose

AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gemcitabine in xenograft models.

Methods

This open-label, Phase I, dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours (NCT00937664). Patients received intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed by AZD7762 plus gemcitabine 1,000 mg/m² on days 1 and 8 of 22-day cycles, in ascending AZD7762 dose cohorts.

Results

Twenty patients received AZD7762 at doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was therefore regarded as non-tolerable. The most common adverse events (AEs) in cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia (45 %) and hypertension, fatigue and rash (30 % each). Grade ≥3 AEs were reported in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to affect AZD7762 PK. There were no objective responses; five patients (all lung cancer) had stable disease.

Conclusions

The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m² was determined as 21 mg in Japanese patients.     

Blood test values and Community Periodontal Index scores in medical checkup recipients

BACKGROUND: We examined the blood test values of people who received general medical checkups and their Community Periodontal Index (CPI) score. METHODS: A total of 7,452 persons (5,742 males and 1,710 females), who had general medical and dental checkups, were the subjects of the study. Many were people who worked for companies in and around Nagoya and their family members, ranging in age from 16 to 80 years. The blood test in our study consisted of 37 items used in general blood tests. Partial-mouth recordings were used to measure CPI scores. The highest CPI score for each subject was used for analysis. Odds ratios and confidence interval values were obtained using the Mantel-Haenszel method to analyze the results. RESULTS: CPI scores of 3 and 4 were related to the test values of high-density-lipoprotein cholesterol, serum iron, white blood cell count, fasting blood sugar, glycosylated hemoglobin A1, glycosylated hemoglobin A1c, and C-reactive protein. CONCLUSION: Blood test values tended to show correlations with CPI scores, more clearly seen in males than in females.