MRI of the Prostate With and Without Endorectal Coil at 3 T: Correlation With Whole-Mount Histopathologic Gleason Score.

OBJECTIVE. The purpose of this article is to prospectively compare image quality and diagnostic accuracy of clinically significant prostate cancer with and without endorectal coil (ERC) at 3 T using a combination of T2-weighted and diffusion-weighted MRI. SUBJECTS AND METHODS. Twenty-three patients with biopsy-proven prostate cancer underwent MRI with and without ERC at the same visit. Patients subsequently underwent radical prostatectomy. Specimens were assessed by whole-mount histopathologic examination. Two radiologists reviewed MR images for image quality (5-point scale) and disease using Prostate Imaging Reporting and Data Systems version 2 (PI-RADSv2). Sensitivity, specificity, and area under the ROC curve (AUC) were calculated with and without ERC. Additionally, apparent diffusion coefficient (ADC) was correlated with Gleason score and ADC values of each lesion were compared with and without ERC. RESULTS. Image quality was comparable with and without ERC (3.8 vs 3.5). Twenty-nine cancer foci larger than 0.5 cm in diameter were found in 23 patients on histopathologic examination; 18 tumors had a Gleason score of 7 or greater. Two radiologists recorded AUC for tumors with a Gleason score of 7 or greater as 0.96 and 0.96 with ERC and 0.88 and 0.91 without ERC. All 13 tumors with a Gleason score of 3 + 4 were detected with ERC, but only 9 were detected without ERC. One of five tumors with Gleason scores less than 3 + 4 was missed with and without ERC. ADC significantly correlated with Gleason score. There was no significant difference in the ADC of a lesion on MRI with and without an ERC. CONCLUSION. MRI with and without ERC was equally accurate at showing prostate cancers with Gleason scores of 4 + 3 or greater. However, MRI with ERC was superior at showing cancer with a Gleason score of 3 + 4. There was no significant difference in ADC values between scores acquired with or without an ERC.

Comparing diagnostic accuracy of luminal water imaging with diffusion-weighted and dynamic contrast-enhanced MRI in prostate cancer: A quantitative MRI study.

Luminal water imaging (LWI) is a new MRI T2 mapping technique that has been developed with the aim of diagnosis of prostate carcinoma (PCa). This technique measures the fractional amount of luminal water in prostate tissue, and has shown promising preliminary results in detection of PCa. To include LWI in clinical settings, further investigation on the accuracy of this technique is required. In this study, we compare the diagnostic accuracy of LWI with those of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) MRI in detection and grading of PCa. Fifteen patients with biopsy-proven PCa consented to participate in this ethics-board-approved prospective study. Patients were examined with LWI, DWI, and DCE sequences at 3 T prior to radical prostatectomy. Maps of MRI parameters were generated and registered to whole-mount histology. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic accuracy of individual and combined MR parameters. Correlation with Gleason score (GS) was evaluated using Spearman's rank correlation test. The results show that area under the ROC curve (AUC) obtained from LWI was equal to or higher than the AUC obtained from DWI, DCE, or their combination, in peripheral zone (0.98 versus 0.90, 0.89, and 0.91 respectively), transition zone (0.99 versus 0.98, n/a, and 0.98), and the entire prostate (0.85 versus 0.81, 0.75, and 0.84). The strongest correlation with GS was achieved from LWI (ρ = -0.81 ± 0.09, P < 0.001). Results of this pilot study show that LWI performs equally well as, or better than, DWI and DCE in detection of PCa. LWI provides significantly higher correlation with GS than DWI and DCE. This technique can potentially be included in clinical MRI protocols to improve characterization of tumors. However, considering the small size of the patient population in this study, a further study with a larger cohort of patients and broader range of GS is required to confirm the findings and draw a firm conclusion on the applicability of LWI in clinical settings.

Assessment of the need for DCE MRI in the detection of dominant lesions in the whole gland: Correlation between histology and MRI of prostate cancer.

The purpose of this study was to evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) in the detection of dominant prostate tumors with multi-parametric MRI of the whole gland. Combined diffusion tensor imaging (DTI) and DCE MRI from 16 patients with biopsy-proven prostate cancer and no previous treatment were acquired with a 3.0-T MRI scanner prior to radical prostatectomy, and used to identify dominant tumors. MRI results were validated by whole-mount histology. Paired t-test and Wilcoxon test, logistic generalized linear mixed effect models and receiver operating characteristic (ROC) analyses were used for the estimation of the statistical significance of the results. In the peripheral zone (PZ), the areas under the ROC curve (ROC-AUC) were 0.98 (sensitivity, 96%; specificity, 98%) for DTI, 0.96 (sensitivity, 92%; specificity, 97%) for DCE and 0.99 (sensitivity, 98%; specificity, 98%) for DTI + DCE. In the entire prostate, the ROC-AUC values were 0.96 (sensitivity, 84%; specificity, 95%) for DTI, 0.87 (sensitivity, 45%; specificity, 94%) for DCE and 0.96 (sensitivity, 88%; specificity, 98%) for DTI + DCE. The increase in ROC-AUC by the addition of DCE was not statistically significant in either PZ or the entire prostate. The results of this study have shown that DTI identified dominant tumors with high accuracy in both PZ and the entire prostate, whereas the inclusion of DCE MRI had no significant impact on the identification of either PZ or entire prostate dominant lesions. Our results suggest that the inclusion of DCE MRI may not increase the accuracy of dominant lesion detection, allowing for faster, better tolerated imaging studies.

Luminal Water Imaging: A New MR Imaging T2 Mapping Technique for Prostate Cancer Diagnosis.

Purpose To assess the feasibility of luminal water imaging, a quantitative T2-based magnetic resonance (MR) imaging technique, for the detection and grading of prostate cancer (PCa). Materials and Methods Eighteen patients with biopsy-proven PCa provided informed consent to be included in this institutional human ethics board-approved prospective study between January 2015 and January 2016. Patients underwent 3.0-T MR imaging shortly before radical prostatectomy. T2 distributions were generated with a regularized non-negative least squares algorithm from multiecho spin-echo MR imaging data. From T2 distributions, maps of seven MR parameters, Ncomp, T2short, T2long, geometric mean T2 (gmT2), luminal water fraction (LWF), Ashort, and Along, were generated and compared with digitized images of hematoxylin-eosin-stained whole-mount histologic slices. A paired t test was used to determine significant differences between MR parameters in malignant and nonmalignant tissue. Correlation with Gleason score (GS) was evaluated with the Spearman rank correlation test. Diagnostic accuracy was evaluated by using logistic generalized linear mixed-effect models and receiver operating characteristic (ROC) analysis. Results The average values of four MR parameters (gmT2, Ashort, Along, and LWF) were significantly different between malignant and nonmalignant tissue. All MR parameters except for T2long showed significant correlation (P < .05) with GS in the peripheral zone. The highest correlation with GS was obtained for LWF (-0.78 ± 0.11, P < .001). ROC analysis demonstrated high accuracy for tumor detection, with the highest area under the ROC curve obtained for LWF (0.97 in the peripheral zone and 0.98 in the transition zone). Conclusion Results of this pilot study demonstrated the feasibility of luminal water imaging in the detection and grading of PCa. A study with a larger cohort of patients and a broader range of GS is required to further evaluate this new technique in clinical settings. © RSNA, 2017.

MR measurement of luminal water in prostate gland: Quantitative correlation between MRI and histology.

PURPOSE: To determine the relationship between parameters measured from luminal water imaging (LWI), a new magnetic resonance imaging (MRI) T2 mapping technique, and the corresponding tissue composition in prostate. MATERIALS AND METHODS: In all, 17 patients with prostate cancer were examined with a 3D multiecho spin echo sequence at 3T prior to undergoing radical prostatectomy. Maps of seven MR parameters, called N, T2-short , T2-long , Ashort , Along , geometric mean T2 time (gmT2 ), and luminal water fraction (LWF), were generated using nonnegative least squares (NNLS) analysis of the T2 decay curves. MR parametric maps were correlated to digitized whole-mount histology sections. Percentage area of tissue components, including luminal space, nuclei, and cytoplasm plus stroma, was measured on the histology sections by using color-based image segmentation. Spearman's rank correlation test was used to evaluate the correlation between MR parameters and the corresponding tissue components, with particular attention paid to the correlation between LWF and percentage area of luminal space. RESULTS: N, T2-short , Along , gmT2 , and LWF showed significant correlation (P < 0.05) with percentage area of luminal space and stroma plus cytoplasm. T2-short and gmT2 also showed significant correlation (P < 0.05) with percentage area of nuclei. Overall, the strongest correlation was observed between LWF and luminal space (Spearman's coefficient of rank correlation = 0.75, P < 0.001). CONCLUSION: Results of this study show that LWF measured with MRI is strongly correlated with the fractional amount of luminal space in prostatic tissue. This result suggests that LWI can potentially be applied for evaluation of prostatic diseases in which the extent of luminal space differs between normal and abnormal tissues. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:861-869.

MR elastography and diffusion-weighted imaging of ex vivo prostate cancer: quantitative comparison to histopathology.

The purpose of this work was (1) to develop a magnetic resonance elastography (MRE) system for imaging of the ex vivo human prostate and (2) to assess the diagnostic power of mono-frequency and multi-frequency MRE and diffusion weighted imaging (DWI) alone and combined as correlated with histopathology in a patient study. An electromagnetic driver was designed specifically for MRE studies in small-bore MR scanners. Ex vivo prostate specimens (post-fixation) of 14 patients who underwent radical prostatectomy were imaged with MRE at 7 T (nine cases had DWI). In six patients, the MRE examination was performed at three frequencies (600, 800, 1000 Hz) to extract the power-law exponent Gamma. The images were registered to wholemount pathology slides marked with the Gleason score. The areas under the receiver-operator-characteristic curves (AUC) were calculated. The methods were validated in a phantom study and it was demonstrated that (i) the driver does not interfere with the acquisition process and (ii) the driver can generate amplitudes greater than 100 µm for frequencies less than 1 kHz. In the quantitative study, cancerous tissue with Gleason score at least 3 + 3 was distinguished from normal tissue in the peripheral zone (PZ) with an average AUC of 0.75 (Gd ), 0.75 (Gl ), 0.70 (Gamma-Gd ), 0.68 (apparent diffusion coefficient, ADC), and 0.82 (Gd + Gl + ADC). The differentiation between PZ and central gland was modest for Gd (p < 0.07), Gl (p < 0.06) but not significant for Gamma (p < 0.2). A correlation of 0.4 kPa/h was found between the fixation time of the prostate specimen and the stiffness of the tissue, which could affect the diagnostic power results. DWI and MRE may provide complementary information; in fact MRE performed better than ADC in distinguishing normal from cancerous tissue in some cases. Multi-frequency (Gamma) analysis did not appear to improve the results. However, in light of the effect of tissue fixation, the clinical implication of our results may be inconclusive and more experiments are needed.

MR elastography of prostate cancer: quantitative comparison with histopathology and repeatability of methods.

The purpose of this work was to assess trans-perineal prostate magnetic resonance elastography (MRE) for (1) repeatability in phantoms/volunteers and (2) diagnostic power as correlated with histopathology in prostate cancer patients. The three-dimensional (3D) displacement field was obtained using a fractionally encoded gradient echo sequence using a custom-made transducer. The repeatability of the method was assessed based on three repeat studies and by changing the driving frequency by 3% in studies on a phantom and six healthy volunteers. Subsequently, 11 patients were examined with MRE prior to radical prostatectomy. The areas under the receiver operating characteristic curves were calculated using a windowed voxel-to-voxel approach by comparing the 2D registered slides, masked with the Gleason score. For the repeatability study, the average intraclass correlation coefficient for elasticity images was 99% for repeat phantom studies, 98% for ±6 Hz phantom studies, 95% for volunteer repeat studies with 2 min acquisition time, 82% for ±2 Hz volunteer studies with 2 min acquisition time and 73% for repeat volunteer studies with 8 min acquisition time. For the patient study, the average elasticity was 8.2 ± 1.7 kPa in the prostate capsule, 7.5 ± 1.9 kPa in the peripheral zone (PZ), 9.7 ± 3.0 kPa in the central gland (CG) and 9.0 ± 3.4 kPa in the transition zone. In the patient study, cancerous tissue with Gleason score at least 3 + 3 was significantly (p < 0.05) different from normal tissue in 10 out of 11 cases with tumors in the PZ, and 6 out of 9 cases with tumors in the CG. However, the overall case-averaged area under the curve was 0.72 in the PZ and 0.67 in the CG. Cancerous tissue was not always stiffer than normal tissue. The inversion algorithm was sensitive to (i) vibration amplitude and displacement nodes and (ii) misalignment of the 3D wave field due to subject movement.

Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer.

Next-generation sequencing is making sequence-based molecular pathology and personalized oncology viable. We selected an individual initially diagnosed with conventional but aggressive prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology-pathology and copy number profiles were remarkably homogeneous, yet it was possible to propose the quadrant of the prostate tumour that likely seeded the metastatic diaspora. Despite a homogeneous cell type, our transcriptome analysis revealed signatures of both luminal and neuroendocrine cell types. Remarkably, the repertoire of expressed but apparently private gene fusions, including C15orf21:MYC, recapitulated this biology. We hypothesize that the amplification and over-expression of the stem cell gene MSI2 may have contributed to the stable hybrid cellular identity. This hybrid luminal-neuroendocrine tumour appears to represent a novel and highly aggressive case of prostate cancer with unique biological features and, conceivably, a propensity for rapid progression to castrate-resistance. Overall, this work highlights the importance of integrated analyses of genome, exome and transcriptome sequences for basic tumour biology, sequence-based molecular pathology and personalized oncology.

From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer.

The current paradigm of cancer care relies on predictive nomograms which integrate detailed histopathology with clinical data. However, when predictions fail, the consequences for patients are often catastrophic, especially in prostate cancer where nomograms influence the decision to therapeutically intervene. We hypothesized that the high dimensional data afforded by massively parallel sequencing (MPS) is not only capable of providing biological insights, but may aid molecular pathology of prostate tumours. We assembled a cohort of six patients with high-risk disease, and performed deep RNA and shallow DNA sequencing in primary tumours and matched metastases where available. Our analysis identified copy number abnormalities, accurately profiled gene expression levels, and detected both differential splicing and expressed fusion genes. We revealed occult and potentially dormant metastases, unambiguously supporting the patients' clinical history, and implicated the REST transcriptional complex in the development of neuroendocrine prostate cancer, validating this finding in a large independent cohort. We massively expand on the number of novel fusion genes described in prostate cancer; provide fresh evidence for the growing link between fusion gene aetiology and gene expression profiles; and show the utility of fusion genes for molecular pathology. Finally, we identified chromothripsis in a patient with chronic prostatitis. Our results provide a strong foundation for further development of MPS-based molecular pathology.

Multiparametric MRI maps for detection and grading of dominant prostate tumors.

PURPOSE: To develop an image-based technique capable of detection and grading of prostate cancer, which combines features extracted from multiparametric MRI into a single parameter map of cancer probability. MATERIALS AND METHODS: A combination of features extracted from diffusion tensor MRI and dynamic contrast enhanced MRI was used to characterize biopsy samples from 29 patients. Support vector machines were used to separate the cancerous samples from normal biopsy samples and to compute a measure of cancer probability, presented in the form of a cancer colormap. The classification results were compared with the biopsy results and the classifier was tuned to provide the largest area under the receiver operating characteristic (ROC) curve. Based solely on the tuning of the classifier on the biopsy data, cancer colormaps were also created for whole-mount histopathology slices from four radical prostatectomy patients. RESULTS: An area under ROC curve of 0.96 was obtained on the biopsy dataset and was validated by a "leave-one-patient-out" procedure. The proposed measure of cancer probability shows a positive correlation with Gleason score. The cancer colormaps created for the histopathology patients do display the dominant tumors. The colormap accuracy increases with measured tumor area and Gleason score. CONCLUSION: Dynamic contrast enhanced imaging and diffusion tensor imaging, when used within the framework of supervised classification, can play a role in characterizing prostate cancer.

Recurrent ectopic pancreatitis of the jejunum and mesentery over a 30-year period.

BACKGROUND: Ectopic pancreas is defined as pancreatic tissue found outside its usual anatomical position, with no ductal or vascular communication with the native pancreas. We describe a case of ectopic pancreas of the small bowel and mesentery causing recurrent episodes of pancreatitis, initially suspected on computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP), and confirmed on histological review of the resection. METHODS: A 67-year-old woman presented with clinical symptoms and biochemical evidence of pancreatitis. She had similar episodes over the past 30 years with unrevealing investigations, and was concluded to have idiopathic pancreatitis. She underwent CT and MRCP, with findings suggestive of ectopic pancreas, a diagnosis confirmed on histology of the resection. RESULTS: MRCP identified a mass in the proximal small bowel mesentery isointense to the native pancreas, with a small duct draining into a proximal jejunal loop. The resected specimen consisted of normal parenchyma with lobulated acinar tissue with scattered islets of Langerhans, an occasional ductular structure, and admixed areas of adipose tissue. The patient remained asymptomatic with normal biochemistry six months post-operatively. CONCLUSION: In an individual with abdominal pain, elevated serum amylase/lipase, but imaging findings of a normal native pancreas, ectopic pancreatitis should be considered, and can be evaluated by CT and MRCP.

Device for sectioning prostatectomy specimens to facilitate comparison between histology and in vivo MRI.

PURPOSE: To develop a device for sectioning prostatectomy specimens that would facilitate comparison between histology and in vivo MRI. MATERIALS AND METHODS: A multi-bladed cutting device was developed, which consists of an adjustable box capable of accommodating a prostatectomy specimen up to 85 mm in size in the lateral direction, a "plunger" tool to press on the excised gland from the top to prevent it from rolling or sliding during sectioning, and a multi-bladed knife assembly capable of holding up to 21 blades at 4-mm intervals. The device was tested on a formalin fixed piece of meat and subsequently used to section a prostatectomy specimen. Histology sections were compared with T2-weighted MR images acquired in vivo before the prostatectomy procedure. RESULTS: The prostatectomy specimen slices were very uniform in thickness with each face parallel to the other with no visible sawing marks on the sections by the blades after the cut. MRI and histology comparison showed good correspondence between the two images. CONCLUSION: The developed device allows sectioning of prostatectomy specimens into parallel cuts at a specific orientation and fixed intervals. Such a device is useful in facilitating accurate correlation between histology and MRI data.

Spontaneous Rupture of Leiomyoma Diagnosed Preoperatively with Noncontrast Computed Tomography.

BACKGROUND: Spontaneous rupture of benign uterine fibroids is extremely rare and has been associated with fibroid degeneration. It can cause acute intraperitoneal bleeding requiring immediate surgical intervention. CASE: A previously healthy 50-year-old, Caucasian, nullipara presented with syncope, hemodynamic instability, and an acute abdomen. Noncontrast computed tomography images showed a positive sentinel clot sign in the pelvis as well as a large uterine fibroid with internal hyperdense clot suggesting acute rupture. Urgent laparotomy and hysterectomy confirmed a ruptured, actively bleeding, uterine fibroid with final pathological diagnosis of a benign leiomyoma. CONCLUSION: Prompt diagnosis and emergency surgical intervention were necessary to control acute hemorrhage from a ruptured uterine fibroid. Noncontrast computed tomography is an important adjunct to contrast-enhanced computed tomography and was vital for diagnosis in this case.

Metastatic Renal Cell Carcinoma to the Testis: A Clinicopathologic Analysis of Five Cases.

The testicular spread of renal cell carcinoma is extremely rare. Five cases of renal cell carcinoma metastatic to the testis are described. The patients ranged from 45 to 81 years of age. Four of the five patients had known renal cell carcinoma. The time intervals between the partial and radical nephrectomies for the primary kidney tumors and the occurrence of testicular metastases ranged from 29 to 34 months. In one patient, the testicular mass was the initial presentation leading to a diagnosis of renal cell carcinoma. There were three ipsilateral metastases, one contralateral metastasis, and one bilateral metastasis. The metastatic deposits ranged in size from 2.0 to 5.7 cm. One case had multiple metastatic tumor nodules. All of the metastatic tumors had clear cell histological features, microscopically concordant with the primary renal cell carcinoma subtype. Three patients died of the disease 17 to 42 months after orchiectomy. One patient is alive with additional metastatic lesions 13 months after orchiectomy. One patient had been free of disease at 87 months after orchiectomy but is now on targeted therapy for an additional metastasis at 93 months after orchiectomy. To date, this report is one of the largest single series of patients with renal cell carcinoma metastatic to the testis, and it has the longest follow-up and survival among all the reported cases.

Metastatic breast carcinoma to the urinary bladder-a report of 11 cases including a tumor to tumor metastasis.

Metastatic breast carcinoma to the urinary bladder is rare. Eleven cases of metastatic breast carcinoma to the bladder are described in this report, including one case with a tumor to tumor metastasis. The patients ranged from 51 to 83 years of age. The time intervals between the diagnosis of primary breast cancer and the occurrence of bladder metastases ranged from 41 to 336 months. There were seven cases of invasive ductal carcinoma and four cases of invasive lobular carcinoma. In one case, a lobular carcinoma of the breast metastasized to a concurrent squamous cell carcinoma of the bladder. The immunophenotypic status of estrogen receptor and Her2 expression of the metastatic carcinomas were all concordant with the primary tumors. In nine patients with follow-up available, seven patients died of the disease ranging from 1 to 23 months after the diagnosis of the bladder metastasis and two patients were alive at 5 months of follow-up. To date, this report is the largest single series of patients with breast carcinoma metastatic to the bladder. It is the first reported instance of lobular carcinoma of the breast metastasizing to a squamous cell carcinoma of the bladder.

Protein profiling of microdissected prostate tissue links growth differentiation factor 15 to prostate carcinogenesis.

Identification of proteomic alterations associated with early stages in the development of prostate cancer may facilitate understanding of progression of this highly variable disease. Matched normal, high-grade prostatic intraepithelial neoplasia (hPIN) and prostate cancer cells of predominantly Gleason grade 3 were procured by laser capture microdissection from serial sections obtained from snap-frozen samples dissected from 22 radical prostatectomy specimens. From these cells, protein profiles were generated by surface-enhanced laser desorption/ionization-time of flight mass spectrometry. A 24-kDa peak was observed at low or high intensity in profiles of prostate cancer cells in 19 of 27 lesions and at low intensity in 3 of 8 hPIN lesions but was not detectable in matched normal cells. SDS-PAGE analysis of prostate cancer and matched normal epithelium confirmed expression of a prostate cancer-specific 24-kDa protein. Mass spectrometry and protein data-based analysis identified the protein as the dimeric form of mature growth differentiation factor 15 (GDF15). The increased expression of mature GDF15 protein in prostate cancer cells cannot be explained on the basis of up-regulation of GDF15 mRNA because reverse transcription-PCR analysis showed similar amounts of transcript in normal, hPIN, and prostate cancer cells that were obtained by laser capture microdissection in the same set of serial sections from which the protein profiles were obtained. Our findings suggest that early prostate carcinogenesis is associated with expression of mature GDF15 protein.

Post-radiation epithelioid angiosarcoma of the urinary bladder and prostate.

Angiosarcoma of the lower urinary tract is exceedingly rare. A minority of cases are associated with local radiotherapy. Epithelioid angiosarcoma is a variant of angiosarcoma composed of large rounded epithelioid endothelial cells that are positive for cytokeratin on immunostaining. There are only two cases of post-radiation epithelioid angiosarcoma reported in the urinary bladder, and none in the prostate gland. We report a case of epithelioid angiosarcoma involving the urinary bladder and prostate in a patient with a history of radiotherapy for prostatic adenocarcinoma. A brief review of literature regarding post-radiation epithelioid angiosarcomas in the lower urinary tract is discussed.

Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells.

PURPOSE: Prostate cancer metastasizes to the skeleton to form osteoblastic lesions. Androgen ablation is the current treatment for metastatic prostate cancer. This therapy is palliative, and the disease will return in an androgen-independent form that is preceded by a rising titer of prostate-specific antigen (PSA). Here, we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen-independent prostate cancer. EXPERIMENTAL DESIGN: Primary cultures of human osteoblasts were used as a source of conditioned medium (OCM). Proliferation, expression of androgen-regulated genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were measured, and its contribution to proliferation and expression of PSA were investigated by neutralization studies with anti IL-6 antibodies. RESULTS: OCM increased the proliferation and expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)- and pARR(3)-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH(2)-terminal domain of the AR. The effect of OCM on transcriptional activity of the AR was inhibited by an antiandrogen. Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM. CONCLUSION: Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer.

The microfracture technique for the treatment of articular cartilage lesions in the knee. A prospective cohort study.

BACKGROUND: Microfracture is a frequently used technique for the repair of articular cartilage lesions of the knee. Despite the popularity of the technique, prospective information about the clinical results after microfracture is still limited. The purpose of our study was to identify the factors that affect the clinical outcome from this cartilage repair technique. METHODS: Forty-eight symptomatic patients with isolated full-thickness articular cartilage defects of the femur in a stable knee were treated with the microfracture technique. Prospective evaluation of patient outcome was performed for a minimum follow-up of twenty-four months with a combination of validated outcome scores, subjective clinical rating, and cartilage-sensitive magnetic resonance imaging. RESULTS: At the time of the latest follow-up, knee function was rated good to excellent for thirty-two patients (67%), fair for twelve patients (25%), and poor for four (8%). Significant increases in the activities of daily living scores, International Knee Documentation Committee scores, and the physical component score of the Short Form-36 were demonstrated after microfracture (p < 0.05). A lower body-mass index correlated with higher scores for the activities of daily living and SF-36 physical component, with the worst results for patients with a body-mass index of >30 kg/m(2). Significant improvement in the activities of daily living score was more frequent with a preoperative duration of symptoms of less than twelve months (p < 0.05). Magnetic resonance imaging in twenty-four knees demonstrated good repair-tissue fill in the defect in thirteen patients (54%), moderate fill in seven (29%), and poor fill in four patients (17%). The fill grade correlated with the knee function scores. All knees with good fill demonstrated improved knee function, whereas poor fill grade was associated with limited improvement and decreasing functional scores after twenty-four months. CONCLUSIONS: Microfracture repair of articular cartilage lesions in the knee results in significant functional improvement at a minimum follow-up of two years. The best short-term results are observed with good fill grade, low body-mass index, and a short duration of preoperative symptoms. A high body-mass index adversely affects short-term outcome, and a poor fill grade is associated with limited short-term durability.

Variation in orthopaedic surgeons' perceptions about the indications for rotator cuff surgery.

BACKGROUND: Epidemiologic studies have demonstrated substantial variations in per capita rates of many surgical procedures, including rotator cuff repair. The purpose of the current study was to characterize orthopaedic surgeons' attitudes concerning medical decision-making about rotator cuff surgery and to investigate the associations between these beliefs and reported surgical volumes. METHODS: A survey was mailed to randomly selected orthopaedic surgeons listed in the American Academy of Orthopaedic Surgeons directory. Only individuals who had treated patients for a rotator cuff tear, or had referred patients for such treatment, within the previous year were asked to complete the two-page survey. The survey comprised fifteen questions regarding clinical opinion, including four regarding hypothetical cases. Clinical agreement was defined as >80% of the respondents answering similarly. RESULTS: Of the 1100 surveys that were mailed, 539 were returned (a response rate of 49%). Of the 539 respondents, 316 (58.6%) had treated or referred patients with a rotator cuff tear in the previous year. There was a significant negative correlation between the surgeon's estimation of the failure rate of cuff repairs in the United States and that surgeon's procedure volume (r = -0.21, p = 0.0003), indicating that surgeons with a lower procedure volume are more pessimistic about the results of surgery than are those with a higher procedure volume. Arthroscopic, mini-open, and open cuff repairs were preferred by 14.5%, 46.2%, and 36.6% of the respondents, respectively. Surgeons who performed a higher volume of procedures were less likely to perform open surgery (p < 0.0001). There was clinical agreement regarding only four of the nine clinical questions and none of the four questions about the hypothetical vignettes. CONCLUSIONS: We found significant variation in surgical decision-making and a lack of clinical agreement among orthopaedic surgeons about rotator cuff surgery. There was a positive correlation between the volume of procedures performed by the surgeon and the surgeon's perception of outcome, with surgeons who had a higher procedure volume being more enthusiastic about rotator cuff surgery than those who had a lower procedure volume.