Immunomodulatory properties of FK734, a humanized anti-CD28 monoclonal antibody with agonistic and antagonistic activities

BACKGROUND: We describe immunomodulatory effects of FK734, a humanized version of a mouse anti-human CD28 mAb (clone TN228), in vitro and in a chimeric human-mouse model of allograft rejection. METHODS: Cytokine production and proliferation were assessed in a mixed lymphocyte reaction containing FK734, human T cells, and endothelial cells or monocytes. FK734 was also administered to SCID mice engrafted with human skin and adoptively transferred with human peripheral blood mononuclear cells allogeneic to the skin graft. RESULTS: In vitro, FK734 enhanced secretion of interleukin-2 and interferon-gamma as well as proliferation of CD4+ and CD8+ T cells stimulated by allogeneic human leukocyte antigen (HLA)-DR+ human umbilical vein endothelial cells (which lack B7 molecules and FcgammaRs) or by blood monocytes (which express low levels of B7 molecules and FcgammaRs) compared with control mAb, but these effects were significantly smaller than those provided by mAb 28.2, a stimulatory mouse anti-human CD28 mAb, at comparable concentrations. However, FK734 generally inhibited cytokine secretion and T cell proliferation in cocultures with human umbilical vein endothelial cells transduced to express CD86. In vivo using SCID/beige mice bearing human skin with adoptively transferred peripheral blood mononuclear cells, administration of FK734 protected human endothelial cell-lined microvessels, significantly but incompletely reducing endothelial cell injury and T cell infiltration into the graft one or two weeks later. CONCLUSIONS: FK734 is a partial agonist of CD28 signaling that can reduce human T cell alloresponses in the presence of strong costimulation by B7 molecules in vitro and can reduce T cell-mediated skin allograft rejection in vivo.     

Idiopathic calcinosis cutis in fingertip treated with occlusive dressing using aluminum foil: a case report.

Calcium deposition in the skin, known as calcinosis cutis, is an uncommon disorder caused by an abnormal deposit of calcium phosphate in the skin. We report a case of idiopathic calcinosis cutis in fingertip treated with surgical excision followed by the occlusive dressing using aluminum foil, and obtained significant pain relief and round-shaped fingertip which looked normal.     

Long-Term Outcomes and Prognostic Factors with Reductive Hepatectomy and Sequential Percutaneous Isolated Hepatic Perfusion for Multiple Bilobar Hepatocellular Carcinoma

Background

Sorafenib is currently recommended as first-line therapy for patients with intermediate or advanced hepatocellular carcinoma (HCC) per Barcelona Clinic Liver Cancer staging. However, the median overall survival (OS) with sorafenib in these patients is 10.7 months with an overall response rate of 2 %. We retrospectively investigated the long-term outcomes and prognostic factors with reductive hepatectomy and sequential percutaneous isolated hepatic perfusion (PIHP) for refractory intermediate or advanced HCC.

Methods

A total of 68 patients who had intermediate or advanced stage HCC without extrahepatic metastases were scheduled for reductive hepatectomy plus PIHP. All patients underwent reductive hepatectomy and PIHP with mitomycin C 20–40 mg/m² and/or doxorubicin 60–120 mg/m² 1–3 months after surgery (mean, 1.51 times/patient).

Results

The objective response rate of PIHP was 70.6 % (complete plus partial response). The median OS of all 68 patients was 25 months, and the 5-year OS rate was 27.6 %. Univariate and multivariate analyses indicated that tumor response to PIHP and normalization of serum des-γ-carboxy prothrombin concentrations after PIHP were independent prognostic factors for OS.

Conclusions

The median OS of the study population treated by reductive hepatectomy and sequential PIHP was 25 months. This treatment strategy can offer a possible curative treatment to patients with refractory intermediate and advanced HCC.     

Rosai-Dorfman disease presenting with multiple intracranial and intraspinal masses: a case report

Rosai-Dorfman disease (RDD), a systemic histioproliferative disorder, was first described by Rosai and Dorfman in 1969. However, only 41 cases involving the central nervous system have been reported. The authors present a rare case of RDD with multiple intracranial and spinal lesions mimicking multiple meningioma. A 59-year-old woman was admitted to our hospital with a history of bilateral visual impairment. MRI demonstrated multiple central nervous system lesions in the suprasellar region, right temporal convexity, left frontal convexity, left cerebello-pontine angle and C5 level of the spinal cord. Preoperative neuro-imaging studies suggested multiple meningioma. Subtotal removal of the suprasellar lesion was performed, followed by gamma knife radiosurgery to the residual lesion and the other intracranial lesions. All intracranial lesions disappeared following gamma knife radiotherapy. The spinal lesion, however, was completely excised one year after the initial operation following the appearance of sensory disturbance. Both intracranial and spinal lesions were diagnosed as RDD on histological examination. No recurrences have been detected on MRI two years after the initial operation. Seeing the good results already achieved by surgical removal of RDD, this case suggests that the combination of surgery and gamma knife radiotherapy might improve further.     

Genetic alteration in carcinoid tumors of the lung.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.     

Evaluation of motion correction effect and image quality with the periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) (BLADE) and parallel imaging acquisition technique in the upper abdomen

PURPOSE: To evaluate motion correction effect and image quality in the upper abdomen with the periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) (BLADE) and parallel imaging acquisition technique. MATERIALS AND METHODS: A total of 50 consecutive patients underwent abdominal MR imaging. Fat-saturated T2-weighted turbo spin-echo sequences were obtained by respiratory triggering. The subjects were examined with three different conditions of echo train length (ETL), blade width, and percent k-space coverage in the same scanning time: 19/30/100%, 30/30/100%, and 30/52/175%, which were designated as L/C(1), L/C(2), and L/C(3), respectively. The parallel imaging acquisition technique was used to either reduce ETL from 30 to 19 in L/C(1) or increase k-space coverage from 100% to 175% in L/C(3) compared with L/C(2). Motion and streak artifacts, and overall image quality were evaluated visually by two radiologists, independently. RESULTS: Motion and streak artifacts were mostly reduced in L/C(3) condition. The L/C(3) image also gave the best overall image quality compared with other conditions (P < 0.001). The inter-rater reliability for each evaluation agreed well. CONCLUSION: In upper abdominal BLADE MRI, it was possible to reduce image artifacts and obtain better image quality by increasing the k-space coverage with parallel imaging in the same scanning time.     

Comparison of plasma levels of mature adrenomedullin and natriuretic peptide as markers of cardiac function in hemodialysis patients with coronary artery disease

BACKGROUND: It has been suggested that, like ANP and BNP, high plasma levels of mature adrenomedullin (mAM) indirectly reflect the severity of heart failure or renal failure. However, the relationship between mAM levels and hemodynamics and cardiac function has not been examined in hemodialysis (HD) patients with coronary artery disease (CAD). The best marker, among mAM, ANP and BNP, for left-ventricular function in those patients is also unclear. PATIENTS AND METHODS: Plasma levels of mAM, total AM (tAM), ANP and BNP were determined before HD in chronic HD patients with CAD (group 1; n = 17) and were compared with those of HD patients without cardiac disease (group 2; n = 22). We examined their relationship to hemodynamics and cardiac function in group 1 using data obtained by cardiac catheterization. RESULTS: Plasma levels of ANP and BNP were significantly higher in group 1 than in group 2, but there was no significant difference in plasma levels of mAM and tAM between the two patient groups. Plasma levels of both mAM and tAM significantly correlated with right atrial pressure (RAP), and only plasma tAM levels correlated with pulmonary artery pressure (PAP) and pulmonary artery wedge pressure (PAWP). However, no correlations were found between levels of the two forms of AM and ejection fraction (EF). In contrast, plasma ANP and BNP levels significantly correlated with both PAP and PAWP, and also with EF, although they did not correlate with RAP. The correlation of PAP and PAWP with ANP and BNP levels was closer than that with tAM levels. The most significant correlation was between BNP levels and EF (r = -0.756, p < 0.0001). CONCLUSIONS: Our results suggest that the mAM level may be less useful than natriuretic peptide levels as a marker of cardiac function in HD patients with CAD, and that the BNP level might be the best indicator of left-ventricular function. In addition, cardiac disease such as CAD may have a minor impact on mAM levels compared to renal failure.     

Relationship among motor function,ADL disability,and psychological concerns in elderly people with locomotive disorders

Background

Locomotive disorders are one of the main causative pathologies for the condition requiring assistance on activities of daily living (ADL). Although psychological concerns such as feeling of depression and anxiety are prevalent in elderly people, the causal relation among motor function, ADL disability, and psychological concerns is controversial.

Survey of volume CT dose index in Japan in 2014

Objective:

The aims of this study are to propose a new set of Japanese diagnostic reference levels (DRLs) for 2014 and to study the impact of tube voltage and the type of reconstruction algorithm on patient doses. The volume CT dose index (CTDI_vol) for adult and paediatric patients is assessed and compared with the results of a 2011 national survey and data from other countries.

Methods:

Scanning procedures for the head (non-helical and helical), chest and upper abdomen were examined for adults and 5-year-old children. A questionnaire concerning the following items was sent to 3000 facilities: tube voltage, use of reconstruction algorithms and displayed CTDI_vol.

Results:

The mean CTDI_vol values for paediatric examinations using voltages ranging from 80 to 100 kV were significantly lower than those for paediatric examinations using 120 kV. For adult examinations, the use of iterative reconstruction algorithms significantly reduced the mean CTDI_vol values compared with the use of filtered back projection. Paediatric chest and abdominal scans showed slightly higher mean CTDI_vol values in 2014 than in 2011. The proposed DRLs for adult head and abdominal scans were higher than those reported in other countries.

Conclusion:

The results imply that further optimization of CT examination protocols is required for adult head and abdominal scans as well as paediatric chest and abdominal scans.

Advances in knowledge:

Low-tube-voltage CT may be useful for reducing radiation doses in paediatric patients. The mean CTDI_vol values for paediatric scans showed little difference that could be attributed to the choice of reconstruction algorithm.Since the introduction of CT in the 1970s, it has been established worldwide as one of the most important imaging modalities in diagnostic radiology. In the past decade, various dose-reduction techniques, such as tube current modulation¹ and low tube voltage,² have been shown to reduce radiation exposure. In particular, the use of an iterative reconstruction (IR) algorithm, in contrast to a filtered back projection (FBP) algorithm, has provided diagnostically acceptable images using low-radiation-dose CT.^3,4Since estimates of the cancer risk attributable to the use of diagnostic X-rays have been reported,^5,6 radiological technologists should aim to optimize scan parameters in order to avoid excessive radiation exposure. One powerful tool in this optimization applies the concept of diagnostic reference levels (DRLs). The DRLs of CT examinations are generally expressed in terms of the volume CT dose index (CTDI_vol) or dose–length product. The DRL is used in medical imaging with ionizing radiation to indicate whether, in routine conditions, the patient dose from a specified procedure is unusually high or low; DRLs are usually reviewed at regular intervals and could be specific to a country or region.⁷ Surveys of DRLs for CT examination of adults^8–11 and children^12,13 have been reported in several countries.The current DRLs in Japan were established as target values by the Japan Association of Radiological Technologists in 2006. The DRLs refer to a set of medical exposure guidelines, although there are several issues with these guidelines.¹⁴ First, no more than two examinations (head and abdomen) are listed in DRLs, and they contain no information about the CT examination of children. Second, the DRL for abdomen examination employs a 30-cm phantom, whereas a 32-cm phantom is more commonly used worldwide. Therefore, a new set of Japanese DRLs has become an urgent necessity. In 2011, Asada et al¹⁵ reported mean CTDI_vol values for the head (non-helical and helical), chest and upper abdomen of both adults and children, which were obtained using a nationally distributed questionnaire. The aims of this study are to propose a new set of Japanese DRLs for 2014 and to study the impact of tube voltage and the type of reconstruction algorithm on patient doses. The CTDI_vol for both adults and children have been assessed and compared with both the results of the 2011 survey and data from other countries.