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.     

Preoperative parameters, including percent of positive biopsy cores, in predicting pathological findings after radical prostatectomy

OBJECTIVES: We investigated whether preoperative parameters predict pathological stage at radical prostatectomy for patients with clinically localized prostatic cancer. MATERIALS AND METHODS: We studied a total of 160 men with clinically localized prostatic cancer (less than or equal to clinical T2) who underwent radical rertropubic prostatectomy at Wakayama Medical University. Clinical Ts patients are not included in this study. Preoperative parameters include patient age, Body Mass Index, preoperative serum PSA value, biopsy Gleason score, clinical stage, the percent of positive biopsy cores (%PosBx) and the percent of positive biopsy cores on the dominant side (%DomPosBx). Univariate and multivariate analysis were performed to examine the prognostic significance of these preoperative parameters. Significant independent factors were combined to create a table to predict pathologically organ confined disease. RESULTS: Univariate analysis showed preoperative serum PSA value (p< 0.001), biopsy Gleason score (p =0.001), clinical stage (p = 0.026), %PosBx (p= 0.002) and %DomPosBx (p=0.003) were significantly related to the pathological stage. On multivariate analysis, serum PSA value (p< 0.01), biopsy Gleason score (p<0.05) and %DomPosBx (p<0.05) were significant independent predictors of pathological stage. CONCLUSION: We provide two model combinations using preoperative clinical factors, one is a combination of serum PSA and biopsy Gleason score and the other is a combination of serum PSA and %DomPosBx, which define a new preoperative model for predicting pathological organ confined prostatic cancer. These combinations are useful and provide important information for urologists to determine the appropriate treatment strategy for clinically localized prostatic cancer.     

Functional Safe Zone Is Superior to the Lewinnek Safe Zone for Total Hip Arthroplasty: Why the Lewinnek Safe Zone Is Not Always Predictive of Stability

Background

The Lewinnek “safe zone” is not always predictive of stability after total hip arthroplasty (THA). Recent studies have focused on functional hip motion as observed on lateral spine-pelvis-hip x-rays. The purpose of this study was to assess the correlation between the Lewinnek safe zone and the functional safe zone based on hip and pelvic motion in the sagittal plane.

Nutrition‐related factors associated with waiting list mortality in patients with interstitial lung disease: A retrospective cohort study

Japanese patients with interstitial lung disease (ILD) sometimes die waiting for lung transplantation (LTx) because it takes about 2 years to receive it in Japan. We evaluated nutrition‐related factors associated with waiting list mortality. Seventy‐six ILD patients were hospitalized in Kyoto University Hospital at registration for LTx from 2013 to 2015. Among them, 40 patients were included and analyzed. Patient background was as follows: female, 30%; age, 50.3 ± 6.9 years; body mass index, 21.1 ± 4.0 kg/m²; 6‐minute walk distance (6MWD), 356 ± 172 m; serum albumin, 3.8 ± 0.4 g/dL; serum transthyretin (TTR), 25.3 ± 7.5 mg/dL; and C‐reactive protein, 0.5 ± 0.5 mg/dL. Median observational period was 497 (range 97‐1015) days, and median survival time was 550 (95% CI 414‐686) days. Survival rate was 47.5%, and mortality rate was 38.7/100 person‐years. Cox analyses showed that TTR (HR 0.791, 95% CI 0.633‐0.988) and 6MWD (HR 0.795, 95% CI 0.674‐0.938) were independently correlated with mortality and were influenced by body fat mass and leg skeletal muscle mass, respectively. It is suggested that nutritional markers and exercise capacity are important prognostic markers in waitlisted patients, but further study is needed to determine whether nutritional intervention or exercise can change outcomes.     

Does Postoperative Complication Have a Negative Impact on Long-Term Outcomes Following Hepatic Resection for Colorectal Liver Metastasis?: A Meta-Analysis

Background

The negative impact of postoperative complications (POCs) on long-term outcomes is well documented for several cancer surgeries, but conclusive evidence has yet to be provided on the influence of POCs on long-term oncological outcomes after hepatic resection for colorectal liver metastasis (CRLM).

Methods

Studies published through February 2012 evaluating the oncological impact of POCs after hepatectomy for CRLM were identified by an electronic literature search. Finally, 4 studies were identified and included in the meta-analysis. The main outcome measures were 5-year disease-free survival (DFS) and overall survival (OS). A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute odds ratio (OR) along with 95 % confidence intervals (95 % CI).

Results

The outcomes of 2,280 patients were studied. Meta-analysis of 5-year DFS data extracted from three studies demonstrated a significant reduction in 5-year DFS after POCs, with an OR of 1.98 (95 % CI = 1.33–2.96; P = .0008). Meta-analysis of 5-year OS data extracted from four studies demonstrated a significant reduction in 5-year OS after POCs, with an OR of 1.68 (95 % CI = 1.25–2.27; P = .0006). No differences between study heterogeneity were observed in either the DFS or the OS analyses.

Conclusions

This study provides persuasive evidence that POCs following hepatic resection for CRLM have significant adverse oncological outcomes. These findings emphasize the need for meticulous surgical technique and careful perioperative management to minimize POCs.     

The relationship between the soluble Klotho protein and the residual renal function among peritoneal dialysis patients

Background

Klotho has been investigated as an anti-aging protein that is predominantly expressed in the distal convoluted tubules in the kidneys and in the choroid plexus of the brain. The purpose of the present study was to determine the relationship between the soluble form of Klotho and renal function in chronic peritoneal dialysis (PD) patients, a relationship which remains poorly understood.

Methods

The soluble Klotho levels in the serum, urine, and peritoneal dialysate obtained from thirty-six PD patients were determined by a sandwich enzyme-linked immunosorbent assay system.

Results

The amount of urinary excreted soluble Klotho over 24?h ranged from 1.54 to 1774.4?ng/day (median 303.2?ng/day; interquartile range [IR] 84.1–498.5), while the serum soluble Klotho concentration ranged from 194.4 to 990.4?pg/ml (mean 553.7?±?210.4?pg/ml). The amount of urinary Klotho excretion was significantly correlated with residual renal function. However, there was no apparent correlation between the serum soluble Klotho levels and the residual renal function. Klotho was also detected in the 24-h dialysate collections. There was a significant correlation between the peritoneal Klotho excretion and the amount of albumin contained in the dialysate collections (r?=?0.798, p?Conclusions The total amount of urinary excreted Klotho, but not the serum level of soluble Klotho, may be a potential biomarker for assessing the residual renal function among PD patients. Whether our findings are also valid for chronic kidney disease patients overall should therefore be evaluated in greater detail.     

Ischemic events due to intraoperative microemboli developing in the cerebral hemisphere contralateral to carotid endarterectomy in a patient with preoperative cerebral hemodynamic impairment

A 74-year-old man with a history of asymptomatic right internal carotid artery (ICA) occlusion experienced amaurosis fugax in the left eye. Angiography showed left cervical ICA stenosis in addition to right cervical ICA occlusion. The right anterior and middle cerebral artery (MCA) territories were perfused from the left ICA via the anterior communicating artery. Brain perfusion single-photon emission computed tomography revealed reduced cerebral blood flow and reduced cerebrovascular reactivity to acetazolamide only in the right cerebral hemisphere. The patient underwent left carotid endarterectomy (CEA). Transcranial Doppler monitoring showed microembolic signals in the left MCA during dissection of the left ICA, but intraoperative monitoring suggested absence of global hypoperfusion or ischemia in the bilateral cerebral hemispheres during left ICA clamping. Transient and slight motor weakness of the left upper extremity was noted on recovery from anesthesia. Diffusion-weighted magnetic resonance imaging demonstrated the development of new spotty ischemic lesions only in the right cerebral hemisphere. The present case suggests that intraoperative cerebral embolism causing postoperative neurological deficits can develop exclusively in the cerebral hemisphere contralateral to CEA if the hemisphere has preoperative hemodynamic impairment and collateral circulation via the anterior communicating artery from the ICA ipsilateral to CEA.     

Surgical outcome of radial osteotomy for Kienböck's disease-minimum 10 years of follow-up

PURPOSE: Long-term results of radial osteotomy for Kienb?ck's disease seldom are seen in the literature. The purpose of this study was to report the minimum 10-year results and to compare them with the 5-year results to determine whether the favorable intermediate-term results were maintained. METHODS: Twenty-five patients who underwent radial osteotomy were followed-up for a mean period of 14.5 years. They were examined for pain, grip strength, and wrist range of motion (ROM). Through a review of clinical records, 5-year postoperative results were collected. The carpal height ratio and St?hl's index were measured and the x-rays were inspected for osteoarthritic changes. We devised an original lunate grade to evaluate radiologic improvement of the ischemic lunate. Overall results were evaluated using Cooney's wrist function score and Nakamura's scoring system for Kienb?ck's disease. The long-term results were compared with both the preoperative status and the 5-year results. RESULTS: Pain, ROM, and grip strength were improved significantly after surgery, and the results were maintained for a long period. Carpal height ratio and St?hl's index did not show significant improvements but ischemic lunate showed certain radiologic improvements with time by the lunate grade system. Osteoarthritic changes were observed in 54% of patients at 5 years and in 73% of patients at the final follow-up evaluation, but the arthrosis generally was mild and did not affect the clinical results. Cooney's wrist function score was excellent or good in 96% of the patients, and the results with Nakamura's scoring system for Kienb?ck's disease were excellent or good in 68% of the patients at the final follow-up evaluation. The percentages were the same 5 years after surgery. CONCLUSIONS: Radial osteotomy for Kienb?ck's disease is a reasonable treatment option and clinical improvement lasts for a long period of time. Although radiologic improvement was not drastic, the inner structure such as sclerotic change or bone cysts of the lunate improved with time, indicating healing of the ischemic lunate. Severe osteoarthritic change or proximal migration of the capitate can be avoided.     

Large Ulcerated Perianal Hidradenoma Papilliferum in a Young Female

BACKGROUND: Hidradenoma papilliferum is an uncommon benign tumor that is located almost exclusively in the vulvar and anal areas. It is usually very small and asymptomatic, and to make a correct diagnosis is clinically very difficult. Occasionally the tumor becomes elevated to form a reddish brown papillary mass, and the surface ulcerates, which may erroneously suggest malignancy. OBJECTIVE: We report a case of a large, perianal hidradenoma papilliferum with suspected malignancy in a young Japanese female. RESULTS: A 22-year-old female had been aware of a perianal nodule for approximately 1 year. Examination of the perianal area revealed a wide pedunculated, reddish nodule with several white maculae. It was ulcerated and bleeding, 2.0 x 1.2 x 0.8 cm in size, and located in the 3 o'clock position. The nodule was totally excised with a narrow margin. The histopathologic diagnosis was hidradenoma papilliferum. No recurrence was observed for 23 months. CONCLUSION: When dermatologists encounter tumors of the anogenital area of adult females, it is important to keep hidradenoma papilliferum in mind as the differential diagnosis. Dermatologists should recognize that the tumor is benign, eliminating the need for wide resection.     

Magnetic resonance cholangiopancreatography for postoperative follow-up of intraductal papillary-mucinous tumors of the pancreas

BACKGROUND: After resection of an intraductal papillary-mucinous tumor (IPMT), benign tumors or portions of the resected tumor are sometimes left in place to avoid total pancreatectomy. We evaluated the role of magnetic resonance cholangiopancreatography (MRCP) in postoperative follow-up. METHODS: Twenty-two patients underwent MRCP 0.5 to 6.5 years after pancreatic resection for IPMT. RESULTS: Two patients with surgical margin involvement of the main pancreatic duct showed mildly enhanced ductal dilatation due to anastomotic stenosis. In 4 patients with residual IPMT of the branch ducts, postoperative MRCP demonstrated no changes. MRCP revealed new IPMT 1 year after surgery in 1 patient. No patients showed intraductal or intracystic mural nodules postoperatively. In 3 patients with postoperative pancreatitis or recurrent abdominal discomfort, MRCP demonstrated ductal dilatation and poor secretin-stimulated pancreatic secretion into the gastrointestinal tract, which suggested pancreatoenterostomic stenosis. CONCLUSIONS: MRCP is useful for postoperative follow-up of IPMT, in terms of investigating residual or recurrent IPMT and evaluating postpancreatectomy long-term complications.