Multiplex protein analysis and ensemble machine learning methods of fine needle aspirates from prostate cancer patients reveal potential diagnostic signatures associated with tumour grade.

BACKGROUND: Improved molecular diagnosis is needed in prostate cancer (PC). Fine needle aspiration (FNA) is a minimally invasive biopsy technique, less traumatic compared to core needle biopsy, and could be useful for diagnosis of PC. Molecular biomarkers (BMs) in FNA-samples can be assessed for prediction, eg of immunotherapy efficacy before treatment as well as at treatment decision time points during disease progression. METHODS: In the present pilot study, the expression levels of 151 BM proteins were analysed by proximity extension assay in FNA-samples from 16 patients, including benign prostate lesions (n = 3) and cancers (n = 13). An ensemble data analysis strategy was applied using several machine learning models. RESULTS: Twelve potentially predictive BM proteins correlating with International Society of Urological Pathology grade groups were identified, among them vimentin, tissue factor pathway inhibitor 2, and integrin beta-5. The validity of the results was supported by network analysis that showed functional associations between most of the identified putative BMs. We also showed that multiple immune checkpoint targets can be assessed (eg PD-L1, CD137, and Galectin-9), which may support the selection of immunotherapy in advanced PC. Results are promising but need further validation in a larger cohort. CONCLUSIONS: Our pilot study represents a "proof of concept" and shows that multiplex profiling of potential diagnostic and predictive BM proteins is feasible on tumour material obtained by FNA sampling of prostate cancer. Moreover, our results demonstrate that an ensemble data analysis strategy may facilitate the identification of BM signatures in pilot studies when the patient cohort is limited.

Carbon Flux as a Measure of Prostate Cancer Aggressiveness: [11C]-Acetate PET/CT.

Purpose: Dynamic [11C]-acetate positron emission tomography (PET) can be used to study tissue perfusion and carbon flux simultaneously. In this study, the feasibility of the quantification of prostate cancer aggressiveness using parametric methods assessing [11C]-acetate kinetics was investigated in prostate cancer subjects. The underlying uptake mechanism correlated with [11C]-acetate influx and efflux measured in real-time in vitro in cell culture. Methods: Twenty-one patients with newly diagnosed low-to-moderate risk prostate cancer underwent magnetic resonance imaging (MRI) and dynamic [11C]-acetate PET/CT examinations of the pelvis. Parametric images of K1 (extraction × perfusion), k2 (oxidative metabolism) and VT (=K1/k2, anabolic metabolism defined as carbon retention) were constructed using a one-tissue compartment model with an arterial input function derived from pelvic arteries. Regions of interest (ROIs) of the largest cancer lesion in each patient and normal prostate tissue were drawn using information from MRI (T2 and DWI images), biopsy results, and post-surgical histopathology of whole prostate sections (n=7). In vitro kinetics of [11C]-acetate were studied on DU145 and PC3 cell lines using LigandTracer® White equipment for the measurement of the radioactivity uptake in real-time at 37°C. Results: Mean prostate specific antigen (PSA) was 8.33±3.92 ng/mL and median Gleason Sum 6 (range 5-7). K1, VT and standardized uptake values (SUVs) were significantly higher in cancerous prostate tissues compared to normal ones for all patients (p<0.001), while k2 was not (p=0.26). PSA values correlated to early SUVs (r=0.50, p=0.02) and K1 (r=0.48, p=0.03). Early and late SUVs correlated to VT (r>0.76, p<0.001) and K1 (r>0.64, p<0.005). In vitro studies demonstrated higher extraction and retention (p<0.01) of [11C]-acetate in the more aggressive PC3 cells. Conclusion: Parametric images could be used to visualize the [11C]-acetate kinetics of the prostate cancer exhibiting elevated extraction associated with the cancer aggressiveness. The influx rate of [11C]-acetate studied in cell culture also showed dependence on the cancer aggressiveness associated with elevated lipogenesis. Dynamic [11C]-acetate/PET demonstrated potential for prostate cancer aggressiveness estimation using parametric-based K1 and VT values.

Pulmonary gas conducting interstitial pathway.

In spite of the growing efforts oriented towards revealing different aspects of emphysema, the persistence of the emphysematous or emphysema-like changes (ELCs) is not explored yet in the open literature. In this study we demonstrate the persistence of an ELC for 22 years in a spontaneous pneumothorax (SP) patient which indicates a hitherto unknown gas supply to the ELC. For this purpose we used high resolution computed tomography (HRCT) images processed into three-dimensional (3D) geometry. By the same token, not only a long persistence but also the volume increase of this ELC between 2002 and 2010 was demonstrated. The 3D geometry visualized an aerated interstitial structure between the sites of supposed gas leakage at the wall of the third generation airways and the ELC. This potential gas conducting interstitial pathway is not a continuation and has neither the form nor the structure of a bronchus. The finding suggests that in this patient the intrabronchial gas passes through the bronchial wall and via a gas conducting interstitial pathway reaches the ELC. Despite the availability of the presently employed techniques for at least 15 years, such case and phenomenon have not been described previously. The retrieval of the patient suggests that the findings could be relevant for a considerable proportion of the population.

Prostate biopsy sampling causes hematogenous dissemination of epithelial cellular material.

The extent of epithelial cellular material (ECM) occurring in venous blood samples after diagnostic core needle biopsy (CNB) was studied in 23 patients with CNB diagnosed prostate cancer without provable metastases and 15 patients without cancer. The data show a significant increase of ECM in the peripheral blood sampled 20 seconds or 30 minutes after the last of 10 CNB procedures compared to the number of ECM detectable in the blood samples taken before the performance of CNB. The data indicate that diagnostic CNB of prostate cancer causes an extensive tissue trauma with a potential risk of cancer cell dissemination.

MR spectroscopy of the human prostate using surface coil at 3 T: metabolite ratios, age-dependent effects, and diagnostic possibilities.

PURPOSE: To measure prostate spectra of healthy volunteers using a surface coil, to demonstrate age-dependent effects, and to investigate diagnostic possibilities for prostate cancer detection. MATERIALS AND METHODS: Single-voxel and 2D magnetic resonance spectroscopic imaging (MRSI) spectra of 51 healthy volunteers with biopsy-proven prostate carcinoma of 20 patients for comparison were measured and processed using the LCModel. The mean normalized spectra and mean metabolite-to-citrate intensity ratios were computed. RESULTS: Metabolite-to-citrate ratios of healthy volunteers were lower in the older group (>51 years) than in the younger group (<45 years). The peripheral zone (PZ) revealed a lower metabolite-to-citrate intensity ratio than the central gland (CG). Age-related differences in metabolite-to-citrate ratio were insignificant in the voxels with predominantly CG tissue, whereas significant differences were found in the PZ. Sensitivity in detecting prostate cancer by single-voxel spectroscopy (SVS) and 2D MRSI was 75% and 80%, respectively. CONCLUSION: SVS and 2D MRSI of the prostate at 3 T, using a surface coil, are useful in situations when insertion of the endorectal coil into the rectum is difficult or impossible. Our findings of age-dependent effects may be of importance for the analysis of patient spectra.

Right main bronchus perforation detected by 3D-image.

A male metal worker, who has never smoked, contracted debilitating dyspnoea in 2003 which then deteriorated until 2007. Spirometry and chest x-rays provided no diagnosis. A 3D-image of the airways was reconstructed from a high-resolution CT (HRCT) in 2007, showing peribronchial air on the right side, mostly along the presegmental airways. After digital subtraction of the image of the peribronchial air, a hole on the cranial side of the right main bronchus was detected. The perforation could be identified at the re-examination of HRCTs in 2007 and 2009, but not in 2010 when it had possibly healed. The occupational exposure of the patient to evaporating chemicals might have contributed to the perforation and hampered its healing. A 3D HRCT reconstruction should be considered to detect bronchial anomalies, including wall-perforation, when unexplained dyspnoea or other chest symptoms call for extended investigation.

Intravenous pamidronate treatment of infants with severe osteogenesis imperfecta.

OBJECTIVE: Children with the severe forms of osteogenesis imperfecta have in several studies been treated with intravenous pamidronate, but there are only few reports of the effect of early treatment. AIM: To evaluate the effect of treatment started in infancy. METHODS: In a prospective observational study, with a historic control group, intravenous disodium pamidronate (APD) was given as monthly infusions to 11 children with osteogenesis imperfecta aged 3-13 (median 3.6) months, who had severe osteogenesis imperfecta with congenital bowing of the femora and vertebral compression fractures. RESULTS: During treatment of children aged between 3 and 6 (median 4.5) years, dual-energy x ray absorptiometry measurements of the lumbar spine showed a gradual increase in bone density. Bone metabolism parameters in serum (alkaline phosphatase, osteocalcin, procollagen 1 carboxy-terminal peptide, collagen 1 teleopeptide) and in urine (deoxypyridinoline) indicated a decrease in bone turnover. An improvement of mobility was seen and at the latest recording, at the age of 3.3-6.5 (median 4.8) years, the children could all walk. Vertebral remodelling was seen, with increased vertebral height, and no child developed scoliosis, kyphosis or basilar impression. All children required femoral intramedullar rods for fractures, and five needed tibial rodding for extreme curvatures that prevented functional standing and walking. No adverse effects were seen on growth, fracture healing or blood chemistry. CONCLUSIONS: APD is an efficient symptomatic treatment for infants with severe osteogenesis imperfecta, but additional orthopaedic surgery is often needed. Early treatment may prevent scoliosis and basilar impression. Long-term follow-up is important.

Impact of radiologic imaging on the surgical decision-making process in suspected appendicitis in children.

RATIONALE AND OBJECTIVES: To evaluate how the surgeons' decision-making process in appendicitis in children is affected by radiologic imaging. MATERIALS AND METHODS: Prospective study including 593 children with suspected appendicitis was conducted. The surgeon's initial clinical disposition was recorded, designating the patient for operation, observation, or discharge. Thereafter, the patients were randomized to undergo either ultrasound only or ultrasound and abdominal computed tomography. The studies were evaluated by radiologists, who indicated if appendicitis was present or not. After radiology was completed, the surgeon re-examined the patient and made the final disposition. The change of disposition pathway was recorded. Final diagnoses were established by means of surgical, histopathologic, and/or clinical follow-up findings. RESULTS: Two hundred forty-four patients had appendicitis. The initial clinical disposition called for 88 operations, 338 observations, and 167 discharges. In total, 347 patients had their treatment plan changed from the initial disposition, resulting in 252 operations, 65 observations, and 276 discharges. In 11 patients, an unnecessary operation was possibly avoided. In 28 patients who turned out to have appendicitis, a possible inappropriate discharge was avoided. Eighteen patients had a false-negative radiologic diagnosis. Of these, 17 underwent surgery because of convincing clinical findings. The difference between the impact on surgeons' decision-making between the two randomized groups was not substantially different. The negative appendectomy rate was 3.7%. CONCLUSION: Radiologic imaging with ultrasound and/or computed tomography provides valuable guidance whether a patient should be discharged, observed, or given surgical treatment, leading to beneficial changes in management plan. Still, false-negative results may occur and a close clinical re-examination is of utmost importance for the appropriate final decision.

Suspected appendicitis in children: diagnosis with contrast-enhanced versus nonenhanced Helical CT.

PURPOSE: To compare the diagnostic accuracy of limited-area (lower abdominal) nonenhanced helical computed tomography (CT), intravenous contrast material-enhanced helical CT of the entire abdomen, and the combination of both. MATERIALS AND METHODS: Three hundred six children suspected of having appendicitis, who were previously included in a prospective study, underwent limited-area nonenhanced helical CT of the lower abdomen and contrast-enhanced CT of the entire abdomen. No oral or rectal contrast material was administered. The CT scans were retrospectively reviewed by three independent readers both separately and together. The readers were blinded to all clinical information and to the results of previous ultrasonographic and CT examinations. Final diagnoses were established on the basis of surgical, histopathologic, or clinical follow-up findings. The Pearson chi(2) test was performed to compare values between groups. The Student two-sample t test was performed to determine statistically significant differences in age and sex. RESULTS: One hundred twenty-nine patients (42%) had appendicitis. Readers diagnosed appendicitis with 66% pooled sensitivity and 96% pooled specificity with limited-area nonenhanced CT. With contrast-enhanced CT of the entire abdomen, appendicitis was diagnosed with 90% pooled sensitivity and 94% pooled specificity. With both sequences together, readers diagnosed appendicitis with 90% pooled sensitivity and 94% pooled specificity. The difference between the sensitivity of limited-area nonenhanced CT and that of contrast-enhanced CT was statistically significant (P <.001). CONCLUSION: Sensitivity of helical CT for suspected appendicitis in children improved significantly with abdominal contrast-enhanced CT compared with limited-area nonenhanced CT. No further improvement in sensitivity was achieved with the combination of both sequences in comparison to that with contrast-enhanced CT alone.

CT in the evaluation of patients on ECMO due to acute respiratory failure.

BACKGROUND: In patients with acute severe respiratory failure (ARF) treated with extracorporeal membrane oxygenation (ECMO) the radiological evaluation has until now almost exclusively relied on bedside radiography and US. At St. Göran/Karolinska ECMO centre CT has become a routine complement to bedside examinations. OBJECTIVE: To review retrospectively the frequency, indications and findings on CT of patients with ARF on ECMO and to evaluate the risk of complications associated with transportation for CT examinations. MATERIALS AND METHODS: One hundred twelve neonates, children and adults were treated with ECMO from May 1994 to January 2001. Forty-six per cent of these patients had CT examinations on one or more occasions during ECMO, giving a total number of 238 examination sites on 104 occasions. All CT examinations were performed in the Paediatric Radiology Department and included a 10-min transport using a mobile ECMO system. RESULTS: CT was more often performed in older patients and in patients with long ECMO runs. The main indications were suspected complications of ECMO and/or the underlying disease or a delay in clinical improvement. In 57% of the CT occasions, significant findings affecting treatment were revealed. There were no complications associated with the examinations or transport. CONCLUSIONS: CT is safe and useful in evaluation of patients with ARF during ECMO.

Suspected appendicitis in children: US and CT--a prospective randomized study.

PURPOSE: To evaluate the accuracy of ultrasonography (US) and of abdominal computed tomography (CT) performed in addition to US in the diagnosis of childhood appendicitis. MATERIALS AND METHODS: Six hundred children with suspected appendicitis were included in a prospective randomized study. After clinical examination, the patients were randomly assigned to undergo US only (283 patients) or US with abdominal CT (317 patients). Radiologic findings were correlated with surgical, histopathologic, and clinical follow-up findings. RESULTS: Two hundred forty-four (40.7%) of all patients had appendicitis. In the US only group, US had a sensitivity of 86%, specificity of 95%, positive predictive value of 91%, negative predictive value of 92%, and diagnostic accuracy of 92%. The combination of US and CT performed in the other group yielded a sensitivity of 99%, specificity of 89%, positive predictive value of 87%, negative predictive value of 99%, and diagnostic accuracy of 93%. Analysis of data on US performed in all 600 patients and on CT performed in 317 patients revealed, respectively, sensitivities of 80% and 97%, specificities of 94% and 93%, positive predictive values of 91% and 92%, negative predictive values of 88% and 98%, and diagnostic accuracies of 89% and 95%. The overall negative appendectomy rate was 3.7%; and the perforation rate, 21%. CONCLUSION: US is valuable in the diagnosis of appendicitis in children. In inconclusive cases, performing additional abdominal CT can improve diagnostic accuracy and thereby decrease the negative appendectomy rate without an increase in the perforation rate.