Epitope mapping human heat shock protein 90 with sera from infected patients

Abstract Epitope mapping with sera from a range of infected patients showed that antibodies are commonly produced which cross-react with a number of epitopes on human heat shock protein 90 (HSP 90). Such autoreactive antibodies were particularly frequent in patients suffering from systemic candidiasis (9 patients), invasive aspergillosis (6 patients), ABPA (2 patients), a patient with aspergilloma and one with malaria. The patient with malaria recognised similar epitopes to those with invasive aspergillosis and candidiasis including the highly conserved epitope LKVIRKVIRK and an epitope NNLGTI which was otherwise only recognised by patients with candidiasis. Crossreacting antibodies to relatively few epitopes occurred in patients with Enterococcus faecalis and Corynebacterium jeikeium endocarditis. This was contrasted with the results from 6 patients with systemic lupus erythematosus (SLE) who were positive on immunoblot against fungal HSP 90. These did not react with the above epitopes but reacted with other areas within human HSP 90.     

Hepatosplenic candidiasis, a late manifestation of Candida septicaemia in neutropenic patients with haematologic malignancies

Systemic candidiasis with Candida-induced abscesses, predominantly in the liver and the spleen, was diagnosed in 27 patients with haematologic malignancies after intensive cytostatic therapy. Specific features included septic fever unresponsive to antimicrobial therapy, hepatosplenomegaly with multiple lesions in the liver and spleen (diameter up to 2 cm) as detected by computed tomography (CT) or ultrasound, and an elevation in liver enzymes. During treatment, induced neutropenia, hepatic and splenic foci were poorly defined histologically and were not identified by imaging procedures. After granulocyte recovery these foci showed characteristic histological patterns. Ultrasound and/or CT investigations of the abdomen now revealed characteristic lesions in the liver and the spleen. Gamma-GT and alkaline phosphatase were early indicators of hepatic involvement in Candida septicaemia and were often already elevated in aplasia.     

Comparison between emission and transmission computed tomography of the liver.

Emission computed tomography (emission CT) and conventional planar gamma-camera imaging of the liver were compared in 242 patients with suspected metastatic spread to liver. Concordant data were obtained in 171 patients (71%). Single large lesions, multiple small lesions, and diffuse disease were accurately defined with this new radionuclide tomographic technique. The smallest lesion detected by emission CT was 8 mm. Emission CT, planar gamma-camera imaging, and transmission (x-ray) CT were compared in 107 patients. All three methods gave identical results in 76 patients (71%). Assessed against other criteria, such as histological findings and follow-up data, emission CT yielded the highest range of accuracy (92-96%), while transmission CT and planar gamma-camera imaging had similar but lower accuracies (78-81%). Emission CT had a false-positive rate of 2.8% and a false-negative rate of less than 1%. Thus emission CT is highly sensitive in detecting space-occupying disease in the liver.     

Value of serum arabinitol for the management of Candida infections in clinical practice

To determine the value of serum arabinitol concentrations in clinical practice, we identified all patients at the University of Utah Medical Center for whom a serum arabinitol determination had been requested by the attending physician or housestaff to assist in the management of candidiasis. The patient populaton was divided into three categories on the basis of clinical and pathological findings: (1) superficial candidiasis, (2) possible deep, invasive candidiasis, and (3) definite, deep invasive candidiasis. Abnormal renal function was associated with elevated concentrations of serum arabinitol in proportion to the degree of renal dysfunction. Both the serum arabinitol concentration and the arabinitol/creatinine ratio were increased in the combined patient population with candidiasis relative to normal uninfected controls (p=0.06 and 0.001, respectively). However, neither of these tests reliably distinguished patients with invasive candidiasis from those with only superficial candidal disease.     

MR扩散加权成像和CT及MR灌注成像对不同程度肝硬化患者的诊断价值

目的:研究MR扩散加权成像(DWI)和CT及MR灌注成像对不同程度肝硬化患者的诊断价值。方法:选择从2015年8月到2017年2月在我院治疗的肝硬化患者60例作为研究对象,根据Child-Pugh分级进行分组,其中A级32例为轻度肝硬化(记为A组),B级16例、C级12例为中重度肝硬化(记为B组),另选同期在我院进行体检的健康志愿者30例记为C组,对三组受试者分别进行DWI检查、CT及MR灌注成像,对比各组ADC值、肝脏动门脉灌注比率[SSr(ct)及SSr(mr)],采用Spearman相关性分析各指标之间的相关性。结果:三组ADC值整体比较无统计学差异(P0.05),A、B两组的ADC值较C组降低,但差异无统计学意义(P0.05)。A、B两组的ADC值比较无统计学差异(P0.05)。三组SSr(ct)、SSr(mr)整体比较,差异有统计学意义(P0.05),B组的SSr(ct)及SSr(mr)较A、C两组明显升高,差异均有统计学意义(均P0.05)。A、C两组的SSr(ct)及SSr(mr)比较无统计学差异(P0.05)。Spearman相关性分析显示,不同程度肝硬化患者的SSr(ct)与SSr(mr)呈正相关(r=0.687,P=0.000)。结论:CT以及MR灌注成像均可较好地反映出肝硬化的病变程度,且二者较DWI成像的诊断效果更佳,值得临床推广。     

Copper toxicosis in non-COMMD1 Bedlington terriers is associated with metal transport gene ABCA12

Wilson’s disease, caused by a mutation in the ATP-ase 7B gene, is the only genetically characterised human disease with inhibition of biliary copper excretion and toxic copper accumulation in liver and occasionally brain. A similar copper toxicosis occurs in Bedlington terriers (CT) with liver damage only. Although CT has been associated with a defect in the COMMD1 gene (COMMD1 ^del/del), Bedlington terriers with CT and lacking this mutation are also recognised (non-COMMD1 ^del/del).A study was designed to identify any other gene polymorphisms associated with copper toxicity in Bedlington terriers employing genome wide association studies (GWAS) followed by deep sequencing of the candidate region. Blood for DNA analysis and liver for confirmation of the diagnosis was obtained from 30 non-COMMD1 ^del/del Bedlington terriers comprising equal numbers of CT-affected dogs and controls. DNA was initially subjected to GWAS screening and then further sequencing to target the putative mutant gene.The study has identified a significant disease association with a region on chromosome 37 containing identified SNP’s which are highly significantly associated with non-COMMD1 ^del/del Bedlington terrier CT. This region contains the ABCA12 gene which bears a close functional relationship to ATP-ase 7B responsible for Wilson’s disease in man.     

Isavuconazole and Liposomal Amphotericin B as Successful Combination Therapy of Refractory Invasive Candidiasis in a Liver Transplant Recipient: A Case Report and Literature Review

Invasive fungal infections in liver transplant recipients are associated with elevated morbidity and mortality and pose a challenge to the treating physicians. Despite of lacking clinical data, the use of antifungal combination therapy is often considered to improve response rates in an immunocompromised patient population. We herein report a case of refractory invasive candidiasis in a liver transplant recipient treated successfully with a combination of isavuconazole und high-dose liposomal amphotericin B. The antimycotic combination treatment was able to clear a bloodstream infection with C. glabrata and led to regression of bilomas among tolerable side effects. The use of the above-mentioned antifungal combination therapy in a liver transplant recipient has not been reported previously. This case highlights the efficacy and safety of antifungal combination therapy in immunocompromised patients with refractory invasive candidiasis.

     

Kinetics of Anti-Mannan Antibodies Useful in Confirming Invasive Candidiasis in Immunocompromised Patients

In studying the anti-mannan antibodies longitudinally in serial serum samples of three immunocompromised patients, it was observed that anti-mannan antibodies started to increase shortly after the moment that cultures of deep-tissue sites became positive with Candida albicans. The mean anti-mannan antibody titers determined in a group of 36 immunocompromised patients with invasive candidiasis increased within two weeks after the probable onset of invasive candidiasis. In contrast, anti-mannan antibody levels in serial serum samples of 14 immunocompromised patients who were only colonized with C. albicans remained stable or decreased over time. The HA test measuring the anti-mannan antibodies was 64% sensitive and 89% specific in determining invasive candidiasis. In contrast, antibodies specific for candidal cytoplasmic antigens or enolase alone were of little value in confirming invasive candidiasis in these immunocompromised patients.     

Microbiological and immunological features of oral candidiasis

Candida albicans(C. albicans) is the major infectious agent of oral candidiasis, and both innate immunity and cell-mediated immune response participate in the control of the fungal infections. The aim of this study was to correlate the clinical forms of oral candidiasis with the number of colony forming units (CFU) of C. albicans in saliva and to characterize T cell response in patients with oral candidiasis. Participants included 75 subjects: 36 with lesions of candidiasis and 39 without lesions of oral candidiasis. A 2-ml sample of saliva was collected from all subjects for microbiological analysis. Cytokine levels were determined by ELISA in supernatants of peripheral blood mononuclear cells of 25 patients with oral candidiasis, after in vitro stimulation with C. albicans antigens. In 48% of patients, no association was observed with denture use. C. albicans was detected in the saliva of 91.7% of patients with oral candidiasis, and there was an association between the number of CFU and the presence of oral lesions. A type Th1 immune response was observed in supernatants of peripheral blood mononuclear cells stimulated with C. albicans antigens. In contrast, IL-5 and IL-10 levels were very low or undetectable. Together, this study shows an association between clinical forms of oral candidiasis and the number of colonies of C. albicans in saliva, and that a systemic immune response characterized by the production of TNF-alpha and IFN-gamma is observed in patients with oral candidiasis.     

Computed tomography for determining liver iron content in primary haemochromatosis.

Dual-energy computed tomography (CT) was used to estimate hepatic iron concentration in eight patients with primary haemochromatosis with varying degrees of iron overload. The values corresponded closely with these derived from chemical analysis of liver tissue obtained by biopsy (correlation coefficient 0.993). Dual-energy CT therefore seems to provide an accurate and non-invasive alternative to liver biopsy as a means of measuring liver iron concentration in patients with primary haemochromatosis and possibly other iron overload states.     

Eficacia del econazol en embarazadas con candidiasis vulvo-vaginal

Among the female patients attending the out patient clinic of the Obstetric Service of the University Hospital of Caracas, Venezuela a hundred were chosen who presented vaginal discharge and itching. The presence of C. albicans and the existence of candidiasis in the vulvo-vagina of the 100 pregnant women was investigated. Those patients where candidiasis was found, were also investigated as to the simultaneous presence of C. albicans in the mouth and the anal skin. Gyno-Pevaryl therapy was performed by administering one 150 mg ovule daily for three consecutive days. At the same time, their partners were treated with Pevaryl 1% cream. The post-therapy control was made 36 hours after conclusion of treatment and further check-up were made one week and two weeks later. Only those patients who attended the post-treatment controls were taken into account for the evaluation of the results. C. albicans was identified in 60 cases by nascent culture of the vulvar secretions, using a bile-agar medium. Of these, 50 had vulvo-vaginal candidiasis (hyphae and blastospores on direct examination). 92% of the women with vulvo-vaginal candidiasis complained about pruritus at the moment of the examination. No significant differences were observed with respect to the age, the period of gestation and parity of the positive and negative patients. Of the 40 patients who attended only the first control, 23 were cured (57.5%), 9 improved (22.5%) and 8 (20%) were not cured. The cure rate increased to 70% and 72.5% taking into account those patients, who also attended the second and the third consecutive treatment sessions, respectively. In those patients suffering from vulvo-vaginal candidiasis, 37.5% were found to be carriers of C. albicans in the mouth and 70% also in the anal region. This seems to indicate that the mouth and the anal region can constitute the source of re-infection in the majority of the cases following topical vaginal treatment.     

Dosimetric impact of contrast-enhanced 4d computed tomography for stereotactic body radiation therapy of hepatocelluar carcinoma

BackgroundA purpose of the study was to investigate the dosimetric impact of contrast media on dose calculation using average 4D contrast-enhanced computed tomography (4D-CECT) and delayed 4D-CT (d4D-CT) images caused by CT simulation contrast agents for stereotactic body radiation therapy (SBRT) of liver cases.Materials and methodsFifteen patients of liver SBRT treated using the volumetric modulated arc therapy (VMAT) technique were selected retrospectively. 4D-CECT, and d4D-CT were acquired with the Anzai gating system and GE CT. For all patients, gross target volume (GTV) was contoured on the ten phases after rigid registration of both the contrast and delayed scans and merged to generate internal target volume (ITV) on average CT images. Region of interest (ROI) was drawn on contrast images and then copied to the delayed images after rigid registration of two average CT datasets. The treatment plans were generated for contrast enhanced average CT, delayed average CT and contrast enhanced average CT with electron density of the heart overridden.ResultsNo significant dosimetric difference was observed in plans parameters (mean HU value of the liver, total monitor units, total control points, degree of modulation and average segment area) except mean HU value of the aorta amongst the three arms. All the OARs were evaluated and resulted in statistically insignificant variation (p > 0.05) using one way ANOVA analysis.ConclusionsContrast enhanced 4D-CT is advantageous in accurate delineation of tumors and assessing accurate ITV. The treatment plans generated on average 4D-CECT and average d4D-CT have a clinically insignificant effect on dosimetric parameters.     

以皮肤受累为首发表现的播散性念珠菌病1例并文献复习

目的：播散性念珠菌病是一种致命性真菌感染性疾病,在免疫缺陷患者中发病率逐年增多,报道1例以双下肢多发皮下结节为首发表现,伴有肺及脑受累的播散性念珠菌病,并文献复习播散性念珠菌病的皮肤受累临床表现。方法患者女,37岁。因双下肢多发皮下结节6个月余就诊。有局灶节段性肾小球硬化病史,口服强的松及他克莫司2a余。取患者皮损组织行病理学检查,皮损组织、脓液、血、痰、尿、粪、脑脊液进行真菌镜检及真菌培养,并文献检索统计播散性念珠菌病皮肤受累患者临床特点。结果皮损组织病理见假菌丝,皮损组织、脓液、痰、尿、粪标本直接涂片均见假菌丝并培养出白念珠菌,CT显示肺受累,诊断为播散性念珠菌病,予抗真菌治疗,患者皮损愈合及肺部病灶部分吸收,但因自行停药,最终出现颅内播散。结论以皮损为首发表现的播散性念珠菌病临床罕见,临床诊疗中应重视应用免疫抑制剂患者皮损的组织病理及微生物检查,及早进行诊断和治疗,防止出现系统性播散,从而降低死亡率。     

T2 magnetic resonance for the diagnosis of deep-seated invasive candidiasis in a liver recipient without candidemia

Background

T2 magnetic resonance imaging (T2MR) is a new method for the diagnosis of invasive candidiasis, although most studies have analyzed its role in patients with candidemia or not infection.

CT与MRI对肝硬化背景下小肝癌检出率的比较

目的:分析比较CT与MR对肝硬化背景下小肝癌检出情况,探究CT与MR在肝硬化背景下小肝癌的诊断价值。方法:选择2010年6月~2015年6月期间,我院收治确诊为肝硬化背景下小肝癌患者91例为研究对象,病理及临床相关方法确诊102个病灶,其中小肝癌69个和微小肝癌33个,患者均在不同时期或序列下行多排螺旋CT与MRI检查,分析比较两者对小肝癌和微小肝癌的检出率。结果:多排螺旋CT检查发现肝癌小病灶91个,其中66个小肝癌,25个微小肝癌;MRI检查发现95个病灶,小肝癌67个,微小肝癌28个;69个小肝癌病灶,检出率最高的为CT动脉期(92.75%)与LAVA动脉期(92.75%),检出率最低的为CT平扫(76.81%);33个微小肝癌病灶,检出率最高为LAVA动脉期(75.76%),检出率最低的为LAVA平衡期(36.36%);CT平扫、门静脉期、动脉期、平衡期、MRI-IN-PHASE、LAVA平衡期、LAVA平扫对小肝癌的检出率显著高于对微小肝癌的检出率(P0.05);CT对小肝癌的检出率显著高于微小肝癌的检出率(P0.05),MRI对小肝癌与微小肝癌的检出率无显著差异(P0.05);MRI与CT对小肝癌的检出率不存在差异(P0.05),但MRI对微小肝癌的检出率显著高于CT(P0.05)。结论:MRI-LAVA的动脉期序列对小肝癌病灶与微小肝癌病灶的检出率最高;CT与MRI在对小肝癌的检出率不存在差异,但MRI对微小肝癌的检出具有更明显的优势。     

Humoral detection of leukaemia-associated antigens in presentation acute myeloid leukaemia

The serological analysis of recombinant cDNA expression libraries (SEREX) technique was used to immunoscreen a testes cDNA expression library with sera from newly diagnosed acute myeloid leukaemia (AML) patients. We used a testis cDNA library to aid our identification of cancer-testis (CT) antigens. We identified 44 antigens which we further immunoscreened with sera from AML, chronic myeloid leukaemia (CML), and normal donors. Eight antigens were solely recognised by patient sera including the recently described CT antigen, PASD1, and the cancer-related SSX2 interacting protein, SSX2IP. RT-PCR analysis indicated that we had identified three antigens which were expressed in patient bone marrow (BM) and peripheral blood (PB) but not in normal donor samples (PASD1, SSX2IP, and GRINL1A). Real-time PCR (RQ-PCR) confirmed the restricted expression of PASD1 in normal donor organs. Antigen presentation assays using monocyte-derived dendritic cells (mo-DCs) showed that PASD1 could stimulate autologous T-cell responses, suggesting that PASD1 could be a promising target for future immunotherapy clinical trials.     

640 层CT 对肝癌碘油栓塞沉积不良的临床分析

目的:探讨640层CT对肝癌碘油栓塞沉积不良患者治疗方案的临床指导。方法:21例富血供肝癌碘油动脉栓塞后,复查肝脏CT病灶内碘油沉积不良患者,用640层螺旋CT行CT灌注成像、CT动脉成像检查。结果:21例碘油沉积不良病灶内仍有动脉血供18例,坏死3例,18例有动脉血供病灶由肝动脉供血6例,膈下动脉供血3例,肠系膜上动脉供血4例,右侧副肾动脉供血1例,胃左动脉供血2例,右肾动脉供血2例。结论:640层螺旋CT灌注成像、CT动脉成像,可以准确显示肿瘤病灶碘油栓塞后肿瘤的残留与坏死,特别能精确判断肿瘤病灶血供起源情况,对再次介入治疗具有重要价值。     

Comprehensive Comparison of Multiple-Detector Computed Tomography and Dynamic Magnetic Resonance Imaging in the Diagnosis of Hepatocellular Carcinoma with Varying Degrees of Fibrosis

Methods841 patients with liver tumor who had liver CT or dynamic MRI examinations followed by surgical resection were included in the study. We defined typical HCC imaging characteristics as early enhancement in the artery phase and early washout in the venous phase. The tumor size was recorded based on pathological examination after surgery. The pathologic fibrosis score was verified by the METAVIR scoring classification.ResultsAmong the 841 patients, 756 underwent liver CT and 204 underwent dynamic liver MRI before surgery. The etiologies of chronic liver disease included hepatitis B virus, hepatitis C virus, hepatitis B and C virus, and non-hepatitis B or C virus. The sensitivity and accuracy of liver CT or MRI for HCC diagnosis was approximately 80%~90%. Liver CT had a diagnostic accuracy for HCC similar to that of dynamic MRI, and liver fibrosis stage did not influence their diagnostic efficacies.ConclusionsThe application of 4-phase dynamic CT and MRI exhibit similar diagnostic accuracy for hepatocellular carcinoma, in tumors of sizes 1 to 2 cm and >2 cm. Liver fibrosis status did not affect the diagnostic accuracy of liver CT or MRI for HCC. The AASLD and EASL restrictions of dynamic imaging studies for HCC diagnosis to cirrhotic patients alone are unnecessary.     

Follow-up computed tomography in patients operated on for liver malignancies

The aim of the investigation was to study a role of computed tomography (CT) in choosing treatment policy for patients after hepatectomy. In 186 patients with liver malignancies, 558 follow-up studies were performed 3 months to 8 years after surgery and adjuvant treatment. RESULTS: the permanent change of the liver, which is detectable at postoperative CT, is its outline deformity. Inverted (87%), irregular (56%), and, less frequently, convex (13%) outlines were identified. Among 41 patients who had postoperatively undergone adjuvant chemoembolization, 7 (17%) patients were seen to have a local compact lipidiol concentration adjacent to the resection plane. CT carried out in 19 patients with suspected postoperative complications could recognize the cause of complications (liver abscesses, abdominal fluid, bilomas) in 15 (78.9%) cases. In 20 patients, compact lipidiol accumulation in the vicinity of the resection plane was the most common, but not pathognomonic sign of tumor resection in the resection plane. Thus, CT plays an important role in the follow-up of patients after liver resections for malignancies in both the early and late postoperative periods.     

Optimization of FDG-PET/CT imaging protocol for evaluation of patients with primary and metastatic liver disease

Background

Accurate determination of the extrahepatic extent and intrahepatic distribution of disease is very important in patients with primary and metastatic liver disease for deciding whether a patient receives potentially curable surgery or palliative treatment. Our objective was to evaluate the efficacy of delayed phase FDG-PET/CT imaging in lesion detection and to define its clinical impact compared to triple-phase contrast enhanced CT (CECT).

Methods

30 patients underwent delayed phase FDG-PET/CT imaging (90 min whole body scan followed by a delayed abdominal scan at 120 min). Maximum standard uptake values (SUVs) and SUV ratios between tumor and normal liver parenchyma (T/N) were evaluated. In addition, comparison was made to CECT obtained within 10 days of the FDG-PET/CT to evaluate for lesion concordance within individual liver segments (Couinaud designation).

Results

Sites of primary malignancies included: colorectal (19), breast (3), pancreas (2), lung (2), carcinoid (2), cholangiocarcinoma (1), and hepatocellular carcinoma (1). There was a significant increase in SUV value of liver lesions between early and delayed acquisition (P < 0.001). Although there was not a significant reduction in liver background activity between the two studies, there was a strong increase in T/N ratio (P < 0.001) allowing better lesion detection by visual inspection. New lesions were identified in 5 of the 30 patients, which were not appreciated on the early scan. Delayed phase FDG-PET/CT identified one lesion which was not present on the corresponding CECT. Delayed phase FDG-PET/CT revealed extrahepatic sites of metastases not appreciated on CECT in 6 patients.

Conclusion

Delayed phase FDG-PET/CT protocol improved lesion detectability in primary and metastatic liver disease, revealing new lesions in 17% of the patients. Moreover, FDG-PET/CT identified extrahepatic disease not seen on CECT in 20% of the patients.