Multianalyte profiling of serum antigens and autoimmune and infectious disease molecules to identify biomarkers dysregulated in epithelial ovarian cancer

Ovarian cancer is the deadliest gynecologic cancer in the United States. When detected early, the 5-year survival rate is 92%, although most cases remain undetected until the late stages where 5-year survival rates are 30%. Serum biomarkers may hold promise. Although many markers have been proposed and multivariate diagnostic models were built to fit the data on small, disparate sample sets, there has been no systematic evaluation of these markers on a single, large, well-defined sample set. To address this, we evaluated the dysregulation of 204 molecules in a sample set consisting of serum from 294 patients, collected from multiple collection sites, under a well-defined Gynecologic Oncology Group protocol. The population, weighted with early-stage cancers to assess biomarker value for early detection, contained all stages of ovarian cancer and common benign gynecologic conditions. The panel of serum molecules was assayed using rigorously qualified, high-throughput, multiplexed immunoassays and evaluated for their independent ovarian cancer diagnostic potential. Seventy-seven biomarkers were dysregulated in the ovarian cancer samples, although cancer antigen 125, C-reactive protein, epidermal growth factor receptor, interleukin 10, interleukin 8, connective tissue growth factor, haptoglobin, and tissue inhibitor of metalloproteinase 1 stood out as the most informative. When analyzed by cancer subtype and stage, there were differences in the relative value of biomarkers. In this study, using a large sample cohort, we show that some of the reported ovarian cancer biomarkers are more robust than others, and we identify additional informative candidates. These findings may guide the development of multivariate diagnostic models, which should be tested on additional, prospectively collected samples.     

Assessment of a daily online implanted fiducial marker‐guided prostate radiotherapy process

The aims of this study were to investigate whether intrafraction prostate motion can affect the accuracy of online prostate positioning using implanted fiducial markers and to determine the effect of prostate rotations on the accuracy of the software‐predicted set‐up correction shifts. Eleven patients were treated with implanted prostate fiducial markers and online set‐up corrections. Orthogonal electronic portal images were acquired to determine couch shifts before treatment. Verification images were also acquired during treatment to assess whether intrafraction motion had occurred. A limitation of the online image registration software is that it does not allow for in‐plane prostate rotations (evident on lateral portal images) when aligning marker positions. The accuracy of couch shifts was assessed by repeating the registration measurements with separate software that incorporates full in‐plane prostate rotations. Additional treatment time required for online positioning was also measured. For the patient group, the overall postalignment systematic prostate errors were less than 1.5 mm (1 standard deviation) in all directions (range 0.2–3.9 mm). The random prostate errors ranged from 0.8 to 3.3 mm (1 standard deviation). One patient exhibited intrafraction prostate motion, resulting in a postalignment prostate set‐up error of more than 10 mm for one fraction. In 14 of 35 fractions, the postalignment prostate set‐up error was greater than 5 mm in the anterior–posterior direction for this patient. Maximum prostate rotations measured from the lateral images varied from 2° to 20° for the patients. The differences between set‐up shifts determined by the online software without in‐plane rotations to align markers, and with rotations applied, was less than 1 mm (root mean square), with a maximum difference of 4.1 mm. Intrafraction prostate motion was found to reduce the effectiveness of the online set‐up for one of the patients. A larger study is required to determine the magnitude of this problem for the patient population. The inability in the current software to incorporate in‐plane prostate rotations is a limitation that should not introduce large errors, provided that the treatment isocentre is positioned near the centre of the prostate.     

Study of internal structure of the human fetus in utero by echo-planar magnetic resonance imaging

The ultrafast echo-planar magnetic resonance imaging technology, developed and built in Nottingham, has been used to produce the first snapshot images of the human fetus in utero. The imager, operating at a proton resonance frequency of 22 MHz, produces transaxial views in 64 or 128 milliseconds. These images comprise either 64 x 128 or 128 x 128 pixels with an in-plane resolution of 3 x 3 mm2. The slice thickness is 10 mm. Fetal scans of up to 32 contiguous slices are produced in a few minutes. These have been used to study the internal structure of the uterus and the fetus in a range of cases with gestations ranging from 26 weeks to term. Echo-planar imaging seems particularly suitable as an imaging modality since its high speed obviates image blurring arising from fetal motion.     

An ultrasonographic study of Peyronie's disease

A study was undertaken to determine the usefulness of ultrasonography as an investigative tool, and its role in deciding the management of Peyronie's disease. Fifteen patients with Peyronie's disease were studied by ultrasonography. The plaque could be demonstrated in all patients. The dimensions of the plaque varied from less than 1 cm to more than 7cm in length and 2-4mm in thickness. The disease was active in 26% of the patients, as indicated by the presence of hypoechoic areas around a central region of hyperechoism. Ultrasonogram was more accurate than clinical assessment in delineating the extent of lesions. In one-third of the patients, sonography demonstrated the plaques to be more extensive than had been detected by clinical examination. Calcification and activity of disease (which are clearly defined by ultrasonogram) are determining factors in the management of Peyronie's disease. This information allows the surgeon to select the modality of treatment, the timing of surgery and extent of excision. Thus, ultrasonography plays a vital role in the preliminary investigation and management of Peyronie's disease.     

Thrombolytic therapy for delayed occlusion of knitted Dacron bypass grafts in the axillofemoral, femoropopliteal and femorotibial positions

Selective intra-arterial streptokinase therapy successfully reopened ten axillofemoral and lower extremity Dacron bypass grafts that had undergone delayed closure from two to 47 months after implantation. In four, completion arteriograms revealed no runoff obstruction acquired since implantation; additional runoff obstruction had developed in the remaining six. All of the grafts without obstruction have remained open from two to 11 months. Three of the six grafts with obstruction have remained open from two and one-half to four months after specific surgical correction of the obstructive lesion. We conclude that intra-arterial streptokinase therapy is an effective means to reopen knitted Dacron grafts that have undergone delayed closure in the axillofemoral and above-knee femoropopliteal positions.     

Transectional echo planar imaging of the heart in cyanotic congenital heart disease

Echo planar imaging is that form of magnetic resonance imaging which gives very short image acquisition times. The method has been used to produce images of the infant heart which are free of cardiorespiratory motion artefact, despite tachypnoea and tachycardia. EPI transections of the normal heart are compared with transections in truncus arteriosus, tetralogy of Fallot, right heart hypoplasia and transposition of the great arteries. The diagnosis of the cause of cyanosis in these infants was established by the noninvasive EPI method and validation of the findings may be found in transectional postmortem analyses reported in the literature. Paper presented at: The Society of Magnetic Resonance in Medicine, London Meeting 1985, and European Society of Paediatric Radiology, Glasgow Meeting 1985     

CuraGen Corporation

CuraGen Scientists have developed a deep preclinical pipeline of potential protein, antibody and small molecule therapeutics by integrating expertise in molecular biology with a proprietary suite of functional genomic technologies. One important application of functional genomics is in the area of pharmacogenomics, which has been a critical component in CuraGen's drug discovery and development efforts. By identifying safety and efficacy issues early in the discovery process and by gaining a better understanding of a drug's mechanism of action, CuraGen scientists are able to make more informed decisions about which drugs are the most appropriate to advance through the preclinical and clinical development stages.     

p53 codon 72 Arg homozygotes are associated with an increased risk of cutaneous melanoma

The p53 gene plays an important role in cell cycle control, facilitating DNA repair activities in response to DNA damage. Aberrant cell cycle control impairs DNA repair and increases the probability of mutations that can lead to carcinogenesis. The p53 gene is polymorphic at codon 72 (Arg/Pro) of its protein, which is functionally distinct, leading to inquiry into its role in carcinogenesis. In this hospital-based case-control study of 289 newly diagnosed patients with melanoma and 308 cancer-free control subjects, we evaluated whether the p53 codon 72 variant is associated with risk of cutaneous melanoma (CM). The controls were frequency-matched to the cases by age, sex, and ethnicity. The frequency of the p53 Arg allele was 78.2% in cases and 73.2% in controls (p=0.045), and the genotype frequencies of p53 Arg/Arg, Arg/Pro, and Pro/Pro were 62.6%, 31.1%, and 6.3%, respectively, in the cases, and 53.9%, 38.6%, and 7.5%, respectively, in the controls (p=0.096). Logistic regression analysis revealed that the p53 Arg/Arg genotype was associated with a significantly increased risk of melanoma (adjusted odds ratio (OR)=1.43; 95% confidence interval (CI)=1.02-2.02) compared with other genotypes, and this association was more evident in subgroups of older subjects (OR=2.32; 95% CI=1.39-388), and subjects with Fitzpatrick's skin type III or IV (OR=1.69; 95% CI=1.11-2.59). In conclusion, this study found some evidence that in subjects over 50, p53 Arg/Arg genotype is associated with increased risk of CM as compared to genotypes Arg/Pro or Pro/Pro. Further larger studies are needed to substantiate our findings.     

Microangiopathic haemolytic anaemia and thrombocytopenia following lung volume reduction surgery in a single lung transplant recipient on maintenance tacrolimus (FK506) therapy

Microangiopathic haemolytic anaemia (MAHA) describes intravascular haemolysis due to mechanical destruction of red cells as a result of pathological changes in small blood vessels. It is well recognized as a complication of cyclosporin A therapy in solid organ transplantation but has been uncommonly reported in association with tacrolimus therapy and never before in the setting of lung transplantation. Discussed is a 54-year-old female recipient of a left single lung transplant who developed anaemia, thrombocytopenia and red blood cell fragmentation consistent with MAHA following lung volume reduction surgery (VRS) of the native right lung in the setting of high serum tacrolimus levels. Treatment with fresh frozen plasma and plasmapharesis plus supportive therapy with blood and platelet transfusions resulted in successful resolution of the haemolytic process. Cyclosporin A was substituted for tacrolimus and 18 months later there has been no evidence of recurrence. Tacrolimus therapy is a rare cause of MAHA in solid organ transplants but the diagnosis should be considered if there is an unexplained fall in haemoglobin and/or platelet count in the context of high serum tacrolimus levels.