Detection, localisation and characterisation of prostate cancer by prostate HistoScanning(™).

UNLABELLED: What's known on the subject? and What does the study add? Prostate cancer is one of the few solid-organ cancers in which imaging is not used in the diagnostic process. Novel functional magnetic resonance imaging techniques offer promise but may not be cost-effective. Prostate HistoScanning(™) (PHS) is an ultrasound-based tissue characterisation technique that has previously shown encouraging results in the detection of clinically significant prostate cancer. The present study reports on the open 'unblinded' phase of a European multicentre study. The prospective 'blind' phase is currently in progress and will determine the value of PHS in a robust fashion overcoming many of the biases inherent in evaluating prostate imaging. OBJECTIVE: To evaluate the ability of prostate HistoScanning(™) (PHS) an ultrasound (US)-based tissue characterization application, to detect cancer foci by correlating results with detailed radical prostatectomy (RP) histology. PATIENT AND METHODS: In all, 31 patients with organ-confined prostate cancer, diagnosed on transrectal biopsies taken using US guidance, and scheduled for RP were recruited from six European centres. Before RP three-dimensional (3D) US raw data for PHS analysis was obtained. Histology by Bostwick Laboratories (London) examined sections obtained from whole mounted glands cut every 3-4 mm. Location and volume estimation of cancer foci by PHS were undertaken using two methods; a manual method and an embedded software tool. In this report we evaluate data obtained from a planned open study phase. The second phase of the study is 'blinded', and currently in progress. RESULTS: 31 patients were eligible for this phase. Three patients were excluded from analysis due to inadequate scan acquisition and pathology violations of the standard operating procedure. One patient withdrew from the study after 3D TRUS examination. PHS detected cancer ≥ 0.20 mL in 25/27 prostates (sensitivity 93%). In all, 23 patients had an index focus ≥ 0.5 mL at pathology, of which 21 were identified as ≥ 0.5 mL by PHS using the manual method (sensitivity 91%) and 19 were correctly identified as ≥ 0.5 mL by the embedded tool (sensitivity 83%). In 27 patients, histological analysis found 32 cancerous foci ≥ 0.2 mL, located in 97 of 162 sextants. After sextant analysis, PHS showed a 90% sensitivity and 72% specificity for the localisation of lesions ≥ 0.2 mL within a sextant. CONCLUSIONS: PHS has the ability to identify and locate prostate cancer and consequently may aid in pre-treatment and pre-surgical planning. In men with a lesion identified, it has potential to enable improved targeting, allowing better risk stratification by obtaining more representative cores. However further verification from the results of the blinded phase of this study are awaited.

Mathematical models to discriminate between benign and malignant adnexal masses: potential diagnostic improvement using ovarian HistoScanning.

PURPOSE: Accurate preoperative clinical assessment of adnexal masses can optimize outcomes by ensuring appropriate and timely surgery. This article addresses whether a new technology, ovarian HistoScanning, has an additional diagnostic value in mathematical models developed for the differential diagnosis of adnexal masses. PATIENTS AND METHODS: Transvaginal sonography-based morphological variables were obtained through blinded analysis of archived images in 199 women enrolled in a prospective study to assess the performance of ovarian HistoScanning. Logistic regression (LR) and neural network (NN) models including these variables and clinical and patient data along with the HistoScanning score (HSS) (range, 0-125; based on mathematical algorithms) were developed in a learning set (60% patients). The remaining 40% patients (evaluation set) were used to assess model performance. RESULTS: Of all morphological and clinical variables tested, serum CA-125, presence of a solid component, and HSS were most significant and used to develop the LR model. The NN model included all variables. The novel variable, HSS, offered significant improvement in the LR and NN models' performance. The LR and NN models in an independent evaluation set were found to have area under the receiver operating characteristic curve = 0.97 (95% confidence interval [CI], 94-99) and 0.93 (95% CI, 88-98), sensitivities = 83% (95% CI, 71%-91%) and 80% (95% CI, 67%-89%), and specificities = 98% (95% CI, 89%-99%) and 86% (95% CI, 72%-95%), respectively. In addition, these models showed an improved performance when compared with 3 other existing models (all P < 0.05). CONCLUSIONS: This initial report shows a clear benefit of including ovarian HistoScanning into mathematical models used for discriminating benign from malignant ovarian masses. These models may be specifically helpful to the less experienced examiner. Future research should assess performance of these models in prospective clinical trials in different populations.

A new computer-aided diagnostic tool for non-invasive characterisation of malignant ovarian masses: results of a multicentre validation study.

OBJECTIVES: To prospectively assess an innovative computer-aided diagnostic technology that quantifies characteristic features of backscattered ultrasound and theoretically allows transvaginal sonography (TVS) to discriminate benign from malignant adnexal masses. METHODS: Women (n = 264) scheduled for surgical removal of at least one ovary in five centres were included. Preoperative three-dimensional (3D)-TVS was performed and the voxel data were analysed by the new technology. The findings at 3D-TVS, serum CA125 levels and the TVS-based diagnosis were compared with histology. Cancer was deemed present when invasive or borderline cancerous processes were observed histologically. RESULTS: Among 375 removed ovaries, 141 cancers (83 adenocarcinomas, 24 borderline, 16 cases of carcinomatosis, nine of metastases and nine others) and 234 non-cancerous ovaries (107 normal, 127 benign tumours) were histologically diagnosed. The new computer-aided technology correctly identified 138/141 malignant lesions and 206/234 non-malignant tissues (98% sensitivity, 88% specificity). There were no false-negative results among the 47 FIGO stage I/II ovarian lesions. Standard TVS and CA125 had sensitivities/specificities of 94%/66% and 89%/75%, respectively. Combining standard TVS and the new technology in parallel significantly improved TVS specificity from 66% to 92% (p < 0.0001). CONCLUSIONS: Computer-aided quantification of backscattered ultrasound is a highly sensitive for the diagnosis of malignant ovarian masses.

Evaluation of Prostate HistoScanning as a Method for Targeted Biopsy in Routine Practice.

BACKGROUND: Prostate HistoScanning (PHS) is a tissue characterization system used to enhance prostate cancer (PCa) detection via transrectal ultrasound imaging. OBJECTIVE: To assess the impact of supplementing systematic transrectal biopsy with up to three PHS true targeting (TT) guided biopsies on the PCa detection rate and preclinical patient assessment. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective study involving a cohort of 611 consecutive patients referred for transrectal prostate biopsy following suspicion of PCa. PHS-TT guided cores were obtained from up to three PHS lesions of ≥0.5cm3 per prostate and only one core per single PHS lesion. Histological outcomes from a systematic extended 12-core biopsy (Bx) scheme and additional PHS-TT guided cores were compared. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comparison of PHS results and histopathology was performed per sextant. The χ2 and Mann-Whitney test were used to assess differences. Statistical significance was set at p<0.05. RESULTS AND LIMITATIONS: PHS showed lesions of ≥0.5cm3 in 312 out of the 611 patients recruited. In this group, Bx detected PCa in 59% (185/312) and PHS-TT in 87% (270/312; p<0.001). The detection rate was 25% (944/3744 cores) for Bx and 68% (387/573 cores) for PHS-TT (p<0.001). Preclinical assessment was significantly better when using PHS-TT: Bx found 18.6% (58/312) and 8.3% (26/312), while PHS-TT found 42.3% (132/312) and 20.8% (65/312) of Gleason 7 and 8 cases, respectively (p<0.001). PHS-TT attributed Gleason score 6 to fewer patients (23.4%, 73/312) than Bx did (32.4%, 101/312; p=0.0021). CONCLUSIONS: Patients with a suspicion of PCa may benefit from addition of a few PHS-TT cores to the standard Bx workflow. PATIENT SUMMARY: Targeted biopsies of the prostate are proving to be equivalent to or better than standard systematic random sampling in many studies. Our study results support supplementing the standard schematic transrectal ultrasound-guided biopsy with a few guided cores harvested using the ultrasound-based prostate HistoScanning true targeting approach in cases for which multiparametric magnetic resonance imaging is not available.

Computer-aided ultrasonography (HistoScanning): a novel technology for locating and characterizing prostate cancer.

OBJECTIVE: To assess the extent to which prostate HistoScanning (PHS), a new ultrasound-based technology that uses computer-aided analysis to quantify tissue disorganization induced by malignant processes, can identify and characterize foci of prostate cancer compared with step-sectioned radical prostatectomy (RP) specimens. PATIENTS AND METHODS: Between September 2004 and February 2006, 29 men had PHS before their scheduled RP. A three-dimensional ultrasound raw-data file was acquired, and PHS analysed regions of interest (ROI) corresponding to tissue volumes of approximately 0.04 mL. In 13 men the histology was examined on sections of the whole-mount prostate onto which a grid of 5 x 5 mm squares was applied. On a test set of 14 of the 29 patients, PHS analysis was used before knowing the histology results (blinded data), to predict the maximum tumour diameter, focality, laterality and extraprostatic extension (EPE). RESULTS: Identification and characterization by PHS of the index tumour in the 14 patients in the test set correlated closely (r = 0.95, P < 0.001) with the reference test. The concordance in the attribution of multifocality (present/absent), unilateral/bilateral disease between PHS and histology was 100%. EPE as determined by PHS was attributed to all three pT3a pathological specimens in the blinded paired data. In the same set of data, EPE was attributed to one prostate cancer that on pathological inspection was deemed to be organ-confined (pT2b). CONCLUSIONS: PHS has the potential to identify and characterize prostate cancer foci noninvasively. The precision appears to be sufficient to suggest that PHS might be useful as a triage test for men deemed to be at risk of prostate cancer and who wish to avoid prostate biopsy.

The accuracy of transrectal ultrasonography supplemented with computer-aided ultrasonography for detecting small prostate cancers.

OBJECTIVE: To determine the extent to which computer-aided ultrasonography of the prostate (HistoScanning, Advanced Medical Diagnostics, Waterloo, Belgium) can identify tumour foci that correspond to a volume of >or=0.50 mL. PATIENTS AND METHODS: Between September 2004 and February 2006, 29 men were HistoScanned before scheduled radical prostatectomy. The three-dimensional raw (grey-scaled) data required for HistoScanning analysis were acquired by transrectal ultrasonography, and analysed using organ-specific tissue-characterization algorithms which form the core of the HistoScanning technology. The HistoScanning analysis results were compared with the histology of the whole-mounted prostate, step-sectioned sagittally at 5-mm intervals, and each slide analysed by 5 x 5 mm grid analysis. RESULTS: Of 29 patients, 13 had histology unknown to those evaluating the HistoScanning data. With 0.50 mL as the lower threshold for delineating and visualizing cancer volume, HistoScanning correctly predicted the presence of all 12 lesions that were subsequently confirmed to occupy >or=0.50 mL. In addition three lesions were predicted as being present and of >or=0.50 mL. These three lesions were subsequently confirmed to be present but were or=0.50 mL; these encouraging results will need to be verified in a larger group of patients.

Using imaging biomarkers to improve the planning of radical prostatectomies.

OBJECTIVES: This exploratory pilot study aimed to evaluate whether adding imaging biomarkers to conventional staging improves complete excision rates after undergoing radical prostatectomy (RP) in the United Kingdom for patients who have not undergone population prostate specific antigen screening. We primarily considered estimates of lesion volume and location based on computer-aided analysis of ultrasound (US) raw radiofrequency (RF) data acquired during trans-rectal ultrasound. The imaging analysis device used had been shown to accurately detect tumor loci within the prostate in previous studies. METHODS AND MATERIALS: US raw RF data were collected from motorized trans-rectal ultrasound of 68 consecutive men with operable prostate cancer. In this cohort (group 1), locations and volume measurements of lesions suspected of harboring cancer on US raw RF data analysis by prostate HistoScanning, were added to conventional presurgical staging.The unexposed control group comprised 100 men who underwent conventional presurgical staging only (group 2): 50 were operated before and 50 operated after group 1 recruitment. Changes to pre-operative surgical planning and positive lateral margins of RP prostate pathological specimens were the primary outcomes. Data were collected using a Microsoft Excel database and analyzed using Stata. RESULTS: Baseline demographics were comparable. In group 1, consideration of the additional imaging biomarkers led to changes in 27 (19.9%) operative surgical plans. Absolute rate reduction of a positive surgical margin (PSM) attributable to the imaging-biomarkers was 13.3% (P = 0.029). For stage pT3, PSM rate was reduced from 45.8% (n = 44) to 21.2% (n = 11) (P = 0.0028). CONCLUSIONS: Obtaining quantitative measurements of preoperative imaging biomarkers appears to improve PSM rates of patients undergoing RP. The greatest PSM rate reduction was observed for pT3 tumors.

A Workflow to Improve the Alignment of Prostate Imaging with Whole-mount Histopathology.

RATIONALE AND OBJECTIVES: Evaluation of prostate imaging tests against whole-mount histology specimens requires accurate alignment between radiologic and histologic data sets. Misalignment results in false-positive and -negative zones as assessed by imaging. We describe a workflow for three-dimensional alignment of prostate imaging data against whole-mount prostatectomy reference specimens and assess its performance against a standard workflow. MATERIALS AND METHODS: Ethical approval was granted. Patients underwent motorized transrectal ultrasound (Prostate Histoscanning) to generate a three-dimensional image of the prostate before radical prostatectomy. The test workflow incorporated steps for axial alignment between imaging and histology, size adjustments following formalin fixation, and use of custom-made parallel cutters and digital caliper instruments. The control workflow comprised freehand cutting and assumed homogeneous block thicknesses at the same relative angles between pathology and imaging sections. RESULTS: Thirty radical prostatectomy specimens were histologically and radiologically processed, either by an alignment-optimized workflow (n = 20) or a control workflow (n = 10). The optimized workflow generated tissue blocks of heterogeneous thicknesses but with no significant drifting in the cutting plane. The control workflow resulted in significantly nonparallel blocks, accurately matching only one out of four histology blocks to their respective imaging data. The image-to-histology alignment accuracy was 20% greater in the optimized workflow (P < .0001), with higher sensitivity (85% vs. 69%) and specificity (94% vs. 73%) for margin prediction in a 5 × 5-mm grid analysis. CONCLUSIONS: A significantly better alignment was observed in the optimized workflow. Evaluation of prostate imaging biomarkers using whole-mount histology references should include a test-to-reference spatial alignment workflow.

A new single-copy mycobacterial plasmid, pMF1, from Mycobacterium fortuitum which is compatible with the pAL5000 replicon.

A 9.2 kb cryptic Mycobacterium fortuitum plasmid, pMF1, was isolated from strain 110 and its restriction map constructed. A 4.2 kb HindIII fragment of pMF1 was found to support replication in mycobacteria and this fragment was cloned and sequenced to characterize the replication elements of the plasmid. Computer analysis identified a putative Rep protein (362 amino acids) with high homology to the putative Rep protein of the Mycobacterium celatum plasmid pCLP and limited homology, mostly in the N-terminal region, to the Rep proteins of Mycobacterium avium pLR7, M. fortuitum pJAZ38 and Mycobacterium scrofulaceum pMSC262. A region containing a putative ori site was located upstream of the rep gene; this region displayed high homology at the nucleotide level with the predicted ori of pCLP and pJAZ38. A plasmid carrying the 4.2 kb HindIII fragment and a kanamycin resistance marker, designated pBP4, was maintained as a single-copy plasmid in Mycobacterium smegmatis and was stably inherited in the absence of antibiotic selection. Plasmid pBP4 was incompatible with the pJAZ38 replicon but was compatible with the widely used pAL5000 replicon, indicating that among the mycobacterial vectors now available there are two incompatibility groups. Significantly, the plasmid was able to replicate in the pathogen Mycobacterium tuberculosis, making it a useful tool for gene expression studies. To provide a choice of restriction sites and easy manipulation, a 2.1 kb fragment containing the minimal replication region was cloned to make the mycobacterial shuttle vector pBP10, which showed similar stability to pBP4.