Case Report: Nontuberculous mycobacterial infections in children with complete DiGeorge anomaly.

Children with complete DiGeorge anomaly (cDGA) have congenital athymia, resulting in severe T cell immunodeficiency and susceptibility to a broad range of infections. We report the clinical course, immunologic phenotypes, treatment, and outcomes of three cases of disseminated nontuberculous mycobacterial infections (NTM) in patients with cDGA who underwent cultured thymus tissue implantation (CTTI). Two patients were diagnosed with Mycobacterium avium complex (MAC) and one patient with Mycobacterium kansasii. All three patients required protracted therapy with multiple antimycobacterial agents. One patient, who was treated with steroids due to concern for immune reconstitution inflammatory syndrome (IRIS), died due to MAC infection. Two patients have completed therapy and are alive and well. T cell counts and cultured thymus tissue biopsies demonstrated good thymic function and thymopoiesis despite NTM infection. Based on our experience with these three patients, we recommend that providers strongly consider macrolide prophylaxis upon diagnosis of cDGA. We obtain mycobacterial blood cultures when cDGA patients have fevers without a localizing source. In cDGA patients with disseminated NTM, treatment should consist of at least two antimycobacterial medications and be provided in close consultation with an infectious diseases subspecialist. Therapy should be continued until T cell reconstitution is achieved.

Photomodulated Extrusion as a Localized Endovascular Hydrogel Deposition Method.

Minimally invasive endovascular embolization is used to treat a wide range of diseases in neurology, oncology, and trauma where the vascular morphologies and corresponding hemodynamics vary greatly. Current techniques based on metallic coils, flow diverters, liquid embolics, and suspended microspheres are limited in their ability to address a wide variety of vasculature and can be plagued by complications including distal migration, compaction, and inappropriate vascular remodeling. Further, these endovascular devices currently offer limited therapeutic functions beyond flow control such as drug delivery. Herein, a novel in situ microcatheter-based photomodulated extrusion approach capable of dynamically tuning the physical and morphological properties of injectable hydrogels, optimizing for local hemodynamic environment and vascular morphology, is proposed and demonstrated. A shear thinning and photoactivated poly(ethylene glycol diacrylate)-nanosilicate (PEGDA-nSi) hydrogel is used to demonstrate multiple extrusion modes which are controlled by photokinetics and device configurations. Real-time photomodulation of injected hydrogel viscosity and modulus is successfully used for embolization in various vasculatures, including high-flow large vessels and arterial-to-arterial capillary shunts. Furthermore, a generalizable therapeutic delivery platform is proposed by demonstrating a core-shell structured extrusion encapsulating doxorubicin to achieve a more sustained release compared to unencapsulated payload.

A Hybrid Human-Machine Learning Approach for Screening Prostate Biopsies Can Improve Clinical Efficiency Without Compromising Diagnostic Accuracy.

CONTEXT.­: Prostate cancer is a common malignancy, and accurate diagnosis typically requires histologic review of multiple prostate core biopsies per patient. As pathology volumes and complexity increase, new tools to improve the efficiency of everyday practice are keenly needed. Deep learning has shown promise in pathology diagnostics, but most studies silo the efforts of pathologists from the application of deep learning algorithms. Very few hybrid pathologist-deep learning approaches have been explored, and these typically require complete review of histologic slides by both the pathologist and the deep learning system. OBJECTIVE.­: To develop a novel and efficient hybrid human-machine learning approach to screen prostate biopsies. DESIGN.­: We developed an algorithm to determine the 20 regions of interest with the highest probability of malignancy for each prostate biopsy; presenting these regions to a pathologist for manual screening limited the initial review by a pathologist to approximately 2% of the tissue area of each sample. We evaluated this approach by using 100 biopsies (29 malignant, 60 benign, 11 other) that were reviewed by 4 pathologists (3 urologic pathologists, 1 general pathologist) using a custom-designed graphical user interface. RESULTS.­: Malignant biopsies were correctly identified as needing comprehensive review with high sensitivity (mean, 99.2% among all pathologists); conversely, most benign prostate biopsies (mean, 72.1%) were correctly identified as needing no further review. CONCLUSIONS.­: This novel hybrid system has the potential to efficiently triage out most benign prostate core biopsies, conserving time for the pathologist to dedicate to detailed evaluation of malignant biopsies.

Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Activation of the PI3K-Akt-mTOR signaling pathway is common in advanced castration resistant prostate cancer (CRPC), typically through PTEN loss. Preclinical studies suggest that Akt-driven CaP cells are genetically susceptible to mammalian target of rapamycin (mTOR, or TORC1) inhibition. Everolimus is a Food and Drug Administration-approved inhibitor of TORC1. MATERIALS AND METHODS: We performed a phase II study of everolimus in patients with mCRPC, who were refractory to standard of care hormonal and chemotherapeutic agents. Patients received everolimus 10 mg daily until unacceptable adverse events or disease progression. The primary efficacy outcome was confirmed 50% or greater prostate-specific antigen (PSA) response, using a 2 stage design with futility rules. Paired biopsies were utilized to assess for treatment effect on downstream TORC1 targets as well as tumor cell proliferation and apoptosis. RESULTS: Out of 35 men enrolled with heavily pretreated mCRPC, 32 were evaluable for clinical efficacy. No PSA responses were observed, the median progression-free survival time was 3.6 months (95% confidence interval = 2.9-4.8) and the median overall survival time was 10.4 months (95% confidence interval = 5.8-15.8). Several patients had declines in serum PSA upon cessation of everolimus. Thus, the study was closed due to clinical futility. The most common toxicities were mucositis, fatigue, anorexia, hypertriglyceridemia, and thrombocytopenia and were largely low grade. Pathologic evaluation of paired metastatic biopsies demonstrated consistent inhibition of pS6, a downstream mTOR pharmacodynamics biomarker, but the tumor proliferation marker Ki-67 increased with therapy. CONCLUSIONS: Everolimus demonstrated predictable toxicity in advanced and heavily pretreated patients with mCRPC. No clinical or clear pathologic effects despite downstream TORC1 target inhibition, suggesting that single agent everolimus has no clinical utility in men with mCRPC.

Metastatic Urothelial Carcinoma from Transplanted Kidney with Complete Response to an Immune Checkpoint Inhibitor.

BACKGROUND: Donor-derived malignancy is a rare complication in patients who undergo organ transplant. Approaches to treatment have largely been individualized based on clinical circumstances given the lack of evidence-based guidelines, with therapeutic options ranging from discontinuation of immunosuppression and transplantectomy to the addition of chemotherapy or radiotherapy. Case Presentation. Herein, we describe a 60-year-old woman with metastatic donor-derived upper tract urothelial carcinoma (UTUC) discovered nine years postrenal transplant. Molecular diagnostic studies using polymerase chain reaction amplification of short tandem repeat alleles and HLA tissue typing proved that the urothelial carcinoma originated from donor tissue. She achieved sustained complete remission with transplant nephroureterectomy, retroperitoneal lymphadenectomy, immunosuppression withdrawal, and immunotherapy with pembrolizumab. Routine radiologic surveillance has demonstrated 15-month progression-free survival to date off pembrolizumab, and she is now under consideration for retransplantation. CONCLUSIONS: Immunotherapy using checkpoint inhibitors can serve as a novel treatment option for patients in the clinical predicament of having a solid organ transplant and simultaneous metastatic malignancy. In this report, we also discuss the oncogenic potential of BK virus, the use of checkpoint inhibitors in urothelial carcinoma, and the feasibility of retransplant for this patient population.

Low-Grade Papillary Schneiderian Carcinoma of the Sinonasal Cavity and Temporal Bone.

OBJECTIVES:: The aim of this study was to further characterize a newly described neoplasm, low-grade papillary Schneiderian carcinoma, occurring simultaneously in the sinonasal cavity and mastoid. Additionally, the authors review the only 2 similar cases within the literature and describe the common clinical features, radiographic findings, and pathologic characteristics of this exceptionally rare disease process. METHODS:: Chart review for single patient, review of literature. RESULTS:: The patient presented with bilateral nasal obstruction. Computed tomography revealed a left sinonasal mass with skull base hyperostosis, and follow-up magnetic resonance imaging showed a concomitant olfactory groove meningioma. Examination showed a bilateral, completely obstructing sinonasal mass with skip areas, and biopsy confirmed inverted papilloma (human papilloma virus strains 16 and 18 indeterminate). The patient underwent bilateral endoscopic sinus surgery, left medial maxillectomy, and left partial nasopharyngectomy. Given her multifocal disease, she was advised that she would require additional excision, but was lost to follow up. One year later she developed acute left facial paralysis. Magnetic resonance imaging demonstrated an enhancing mass in the left mastoid with enhancement along the Eustachian tube in addition to her known recurrent sinonasal disease. Simultaneous endoscopic sinus surgery and mastoidectomy were performed. Polypoid tissue was removed from the nasopharynx, mesotympanum, epitympanum, and retrofacial air cells. Immunohistochemistry showed that cells stained positive for p63 and dermCK and negative for synaptophysin. Morphologically, cells were bland, without classic stromal invasion, retaining their smooth, cystic, and papillary features, despite their increased depth within the tissue. Upon further review and consultation with an outside pathologist, a diagnosis of low-grade papillary Schneiderian carcinoma was made. The patient was referred for radiation therapy and is disease free at 3-month follow-up, with return of her facial function. CONCLUSIONS:: This case represents the first report of concurrent low-grade papillary Schneiderian carcinoma of both the nasal cavity and mastoid. It emphasizes the importance of recognizing this new entity through pathologic analysis and suspecting it when the clinical course does not follow an expected pattern.

Wilms Tumor After Orthotopic Liver Transplant in a Patient With Alagille Syndrome.

We present a case of Wilms Tumor in a patient with Alagille syndrome 10 months after liver transplant. We explore a suggested genetic connection between these 2 diseases. In children with Wilms Tumor, we propose a pathoembryologic explanation for not just the tumor, but also for the cause of associated benign ureteral and renal parenchymal aberrancies that are commonly seen in the Alagille population. We also discuss the diagnostic and therapeutic challenges that can arise in a liver transplant patient with Alagille syndrome who subsequently develops a renal mass.

Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection.

Mycobacterium tuberculosis infection in humans triggers formation of granulomas, which are tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden, and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response.

Can Radiologic Staging With Multiparametric MRI Enhance the Accuracy of the Partin Tables in Predicting Organ-Confined Prostate Cancer?

OBJECTIVE: The purpose of this study is to investigate the accuracy of multiparametric MRI with endorectal coil and Partin tables in predicting organ-confined (OC) prostate cancer in a contemporary cohort undergoing radical prostatectomy (RP) and to assess the possible added value of radiologic staging based on multiparametric MRI to the predictive accuracy of Partin tables. MATERIALS AND METHODS: One hundred fifty-eight consecutive subjects underwent 3-T multiparametric MRI with endorectal coil before RP between November 2010 and November 2013. Data were randomly split 60% and 40% into derivation (n = 95) and validation (n = 62) datasets. Multiparametric MRI was used to assess the radiologic stage, and logistic regression models were created using the derivation dataset and were fit on the independent validation dataset using multiparametric MRI staging alone and with prostate-specific antigen (PSA) level as the covariate. The probability of each patient to harbor OC disease was calculated using an updated version of Partin tables, using either clinical staging from digital rectal examination (DRE) or radiologic staging (multiparametric MRI). The AUC was calculated to evaluate accuracy of these predictive methods. RESULTS: The accuracy of multiparametric MRI to predict OC disease on pathologic analysis was greater (AUC, 0.88) than that of Partin tables (AUC, 0.70) and improved when multiparametric MRI was combined with PSA level (AUC, 0.91). The accuracy of Partin nomograms to predict OC disease decreased (AUC, 0.63) when staging was based on multiparametric MRI versus DRE. CONCLUSION: The superior predictive accuracy of multiparametric MRI compared with Partin tables to predict OC disease validates the results of smaller previously published studies. Although there is no added benefit of substituting multiparametric MRI stage for clinical stage when using Partin tables, multiparametric MRI staging information is valuable as a stand-alone test.

Identifying Clinically Significant Prostate Cancers using 3-D In Vivo Acoustic Radiation Force Impulse Imaging with Whole-Mount Histology Validation.

Overly aggressive prostate cancer (PCa) treatment adversely affects patients and places an unnecessary burden on our health care system. The inability to identify and grade clinically significant PCa lesions is a factor contributing to excessively aggressive PCa treatment, such as radical prostatectomy, instead of more focal, prostate-sparing procedures such as cryotherapy and high-dose radiation therapy. We have performed 3-D in vivo B-mode and acoustic radiation force impulse (ARFI) imaging using a mechanically rotated, side-fire endorectal imaging array to identify regions suspicious for PCa in 29 patients being treated with radical prostatectomies for biopsy-confirmed PCa. Whole-mount histopathology analyses were performed to identify regions of clinically significant/insignificant PCa lesions, atrophy and benign prostatic hyperplasia. Regions of suspicion for PCa were reader-identified in ARFI images based on boundary delineation, contrast, texture and location. These regions of suspicion were compared with histopathology identified lesions using a nearest-neighbor regional localization approach. Of all clinically significant lesions identified on histopathology, 71.4% were also identified using ARFI imaging, including 79.3% of posterior and 33.3% of anterior lesions. Among the ARFI-identified lesions, 79.3% corresponded to clinically significant PCa lesions, with these lesions having higher indices of suspicion than clinically insignificant PCa. ARFI imaging had greater sensitivity for posterior versus anterior lesions because of greater displacement signal-to-noise ratio and finer spatial sampling. Atrophy and benign prostatic hyperplasia can cause appreciable prostate anatomy distortion and heterogeneity that confounds ARFI PCa lesion identification; however, in general, ARFI regions of suspicion did not coincide with these benign pathologies.

Apparent Diffusion Coefficient Values of the Benign Central Zone of the Prostate: Comparison With Low- and High-Grade Prostate Cancer.

OBJECTIVE: The apparent diffusion coefficient (ADC) values for benign central zone (CZ) of the prostate were compared with ADC values of benign peripheral zone (PZ), benign transition zone (TZ), and prostate cancer, using histopathologic findings from radical prostatectomy as the reference standard. MATERIALS AND METHODS: The study included 27 patients with prostate cancer (mean [± SD] age, 60.0 ± 7.6 years) who had 3-T endorectal coil MRI of the prostate performed before undergoing prostatectomy with whole-mount histopathologic assessment. Mean ADC values were recorded from the ROI within the index tumor and within benign CZ, PZ, and TZ, with the use of histopathologic findings as the reference standard. ADC values of the groups were compared using paired t tests and ROC curve analysis. RESULTS: The ADC of benign CZ in the right (1138 ± 123 × 10(-6) mm(2)/s) and left (1166 ± 141 × 10(-6) mm(2)/s) lobes was not significantly different (p = 0.217). However, the ADC of benign CZ (1154 ± 129 × 10(-6) mm(2)/s) was significantly lower (p < 0.001) than the ADCs of benign PZ (1579 ± 197 × 10(-6) mm(2)/s) and benign TZ (1429 ± 180 × 10(-6) mm(2)/s). Although the ADC of index tumors (1042 ± 134 × 10(-6) mm(2)/s) was significantly lower (p = 0.002) than the ADC of benign CZ there was no significant difference (p = 0.225) between benign CZ and tumors with a Gleason score of 6 (1119 ± 87 × 10(-6) mm(2)/s). In 22.2% of patients (6/27), including five patients who had tumors with a Gleason score greater than 6, the ADC was lower in benign CZ than in the index tumor. The AUC of ADC for the differentiation of benign CZ from index tumors was 72.4% (sensitivity, 70.4%; specificity, 51.9%), and the AUC of ADC for differentiation from tumors with a Gleason score greater than 6 was 76.7% (sensitivity, 75.0%; specificity, 65.0%). CONCLUSION: The ADC of benign CZ is lower than the ADC of other zones of the prostate and overlaps with the ADC of prostate cancer tissue, including high-grade tumors. Awareness of this potential diagnostic pitfall is important to avoid misinterpreting the normal CZ as suspicious for tumor.

B-mode and acoustic radiation force impulse (ARFI) imaging of prostate zonal anatomy: comparison with 3T T2-weighted MR imaging.

Prostate cancer (PCa) is the most common non-cutaneous malignancy among men in the United States and the second leading cause of cancer-related death. Multi-parametric magnetic resonance imaging (mpMRI) has gained recent popularity to characterize PCa. Acoustic Radiation Force Impulse (ARFI) imaging has the potential to aid PCa diagnosis and management by using tissue stiffness to evaluate prostate zonal anatomy and lesions. MR and B-mode/ARFI in vivo imaging datasets were compared with one another and with gross pathology measurements made immediately after radical prostatectomy. Images were manually segmented in 3D Slicer to delineate the central gland (CG) and prostate capsule, and 3D models were rendered to evaluate zonal anatomy dimensions and volumes. Both imaging modalities showed good correlation between estimated organ volume and gross pathologic weights. Ultrasound and MR total prostate volumes were well correlated (R(2) = 0.77), but B-mode images yielded prostate volumes that were larger (16.82% ± 22.45%) than MR images, due to overestimation of the lateral dimension (18.4% ± 13.9%), with less significant differences in the other dimensions (7.4% ± 17.6%, anterior-to-posterior, and -10.8% ± 13.9%, apex-to-base). ARFI and MR CG volumes were also well correlated (R(2) = 0.85). CG volume differences were attributed to ARFI underestimation of the apex-to-base axis (-28.8% ± 9.4%) and ARFI overestimation of the lateral dimension (21.5% ± 14.3%). B-mode/ARFI imaging yielded prostate volumes and dimensions that were well correlated with MR T2-weighted image (T2WI) estimates, with biases in the lateral dimension due to poor contrast caused by extraprostatic fat. B-mode combined with ARFI imaging is a promising low-cost, portable, real-time modality that can complement mpMRI for PCa diagnosis, treatment planning, and management.

Evaluation of cold ischemia for preservation of testicular function during partial orchiectomy in the rat model.

OBJECTIVE: We hypothesized that cold ischemia during partial orchiectomy would lead to higher serum testosterone levels and preservation of testicular architecture than warm ischemia in a prepubescent rat model. MATERIALS AND METHODS: Eighteen prepubescent male Sprague-Dawley rats were randomized to three different surgical groups: sham surgery, bilateral partial orchiectomy with 30 min of cord compression with cold ischemia, or bilateral partial orchiectomy with 30 min of cord compression with warm ischemia. Animals were killed at puberty, and serum, sperm, and testicles were collected. Histological tissue injury was graded by standardized methodology. RESULTS: Mean serum testosterone levels were 1445 ± 590 pg/mL for the sham group, 449 ± 268 pg/mL for the cold ischemia group and 879 ± 631 pg/mL for the warm ischemia group (p = 0.12). Mean sperm counts were 2.1 × 10(7) for sham, 4.4 × 10(6) for cold ischemia, and 9.9 × 10(6) for the warm ischemia groups (p = 0.48). Histological evaluation revealed significant difference in tissue injury grading with more injury in the cold ischemia than in the warm ischemia group (p = 0.01). CONCLUSIONS: In our preclinical rat model, we found no benefit for cold ischemia over warm ischemia at 30 min.

Comparing 3-T multiparametric MRI and the Partin tables to predict organ-confined prostate cancer after radical prostatectomy.

OBJECTIVES: The purpose of our study was to test our hypothesis that multiparametric magnetic resonance imaging (mpMRI) may have a higher prognostic accuracy than the Partin tables in predicting organ-confined (OC) prostate cancer and extracapsular extension (ECE) after radical prostatectomy (RP). METHODS AND MATERIALS: After institutional review board approval, we retrospectively reviewed 60 patients who underwent 3-T mpMRI before RP. mpMRI was used to assess clinical stage and the updated version of the Partin tables was used to calculate the probability of each patient to harbor OC disease. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of mpMRI in detecting OC and ECE were calculated. Logistic regression models predicting OC pathology were created using either clinical stage at mpMRI or Partin tables probability. The area under the curve was used to calculate the predictive accuracy of each model. RESULTS: Median prostate-specific antigen level at diagnosis was 5 ng/ml (range: 4.1-6.7 ng/ml). Overall, 52 (86.7%) men had cT1 disease, 7 (11.7%) had cT2a/b, and 1 (1.6%) had cT3b at digital rectal examination. Biopsy Gleason score was 6, 3+4 = 7, 4+3 = 7, 8, and 9 to 10 in 28 (46.7%), 15 (25%), 3 (5%), 10 (16.7%), and 4 (6.6%) patients, respectively. At mpMRI, clinical stage was defined as cT2a/b, cT2c, cT3a, and cT3b in 11 (18.3%), 23 (38.3%), 21 (35%), and 5 (8.4%) patients, respectively. At final pathology, 38 men (63.3%) had OC disease, whereas 18 (30%) had ECE and 4 (6.7%) had seminal vesicle invasion. The sensitivity, specificity, PPV, and NPV of mpMRI in detecting OC disease were 81.6%, 86.4%, 91.2%, and 73.1%, respectively, whereas in detecting ECE were 77.8%, 83.4%, 66.7%, and 89.7%, respectively. At logistic regression, both the Partin tables-derived probability and the mpMRI clinical staging were significantly associated with OC disease (all P<0.01). The area under the curves of the model built using the Partin tables and that of the mpMRI model were 0.62 and 0.82, respectively (P = 0.04). CONCLUSIONS: The predictive accuracy of mpMRI in predicting OC disease on pathological analysis is significantly greater than that of the Partin tables. mpMRI had a high PPV (91.2%) when predicting OC disease and a high NPV (89.7%) with regard to ECE. mpMRI should be considered when planning prostate cancer treatment in addition to readily available clinical parameters.

Small renal mass biopsy--how, what and when: report from an international consensus panel.

To discuss the use of renal mass biopsy (RMB) for small renal masses (SRMs), formulate technical aspects, outline potential pitfalls and provide recommendations for the practicing clinician. The meeting was conducted as an informal consensus process and no scoring system was used to measure the levels of agreement on the different topics. A moderated general discussion was used as the basis for consensus and arising issues were resolved at this point. A consensus was established and lack of agreement to topics or specific items was noted at this point. Recommended biopsy technique: at least two cores, sampling different tumour regions with ultrasonography being the preferred method of image guidance. Pathological interpretation: 'non-diagnostic samples' should refer to insufficient material, inconclusive and normal renal parenchyma. For non-diagnostic samples, a repeat biopsy is recommended. Fine-needle aspiration may provide additional information but cannot substitute for core biopsy. Indications for RMB: biopsy is recommended in most cases except in patients with imaging or clinical characteristics indicative of pathology (syndromes, imaging characteristics) and cases whereby conservative management is not contemplated. RMB is recommended for active surveillance but not for watchful-waiting candidates. We report the results of an international consensus meeting on the use of RMB for SRMs, defining the technique, pathological interpretation and indications.

Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer--factors affecting diagnostic success.

PURPOSE: To determine the rate at which computed tomographically guided pelvic percutaneous bone biopsy in men with metastatic castration-resistant prostate cancer (mCRPC) yields adequate tissue for genomic profiling and to identify issues likely to affect diagnostic yields. MATERIALS AND METHODS: This study was institutional review board approved, and written informed consent was obtained. In a phase II trial assessing response to everolimus, 31 men with mCRPC underwent 54 biopsy procedures (eight men before and 23 men both before and during treatment). Variables assessed were lesion location (iliac wing adjacent to sacroiliac joint, iliac wing anterior and/or superior to sacroiliac joint, sacrum, and remainder of pelvis), mean lesion attenuation, subjective lesion attenuation (purely sclerotic vs mixed), central versus peripheral lesion sampling, lesion size, core number, and use of zoledronic acid for more than 1 year. RESULTS: Of 54 biopsy procedures, 21 (39%) yielded adequate tissue for RNA isolation and genomic profiling. Three of four sacral biopsies were adequate. Biopsies of the ilium adjacent to the sacroiliac joints were more likely adequate than those from elsewhere in the ilium (48% vs 28%, respectively). All five biopsies performed in other pelvic locations yielded inadequate tissue for RNA isolation. Mean attenuation of lesions with inadequate tissue was 172 HU greater than those with adequate tissue (621.1 HU ± 166 vs 449 HU ± 221, respectively; P = .002). Use of zoledronic acid, peripheral sampling, core number, and lesion size affected yields, but the differences were not statistically significant. Histologic examination with hematoxylin-eosin staining showed that results of 36 (67%) biopsies were positive for cancer; only mean attenuation differences were significant (707 HU ± 144 vs 473 HU ± 191, negative vs positive, respectively; P < .001). CONCLUSION: In men with mCRPC, percutaneous sampling of osseous metastases for genomic profiling is possible, but use of zoledronic acid for more than 1 year may reduce the yield of adequate tissue for RNA isolation. Sampling large low-attenuating lesions at their periphery maximizes yield.

Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer.

Enterolactone and enterodiol, mammalian lignans derived from dietary sources such as flaxseed, sesame seeds, kale, broccoli, and apricots, may impede tumor proliferation by inhibiting activation of nuclear factor kappa B (NFκB) and vascular endothelial growth factor (VEGF). We examined the associations between urinary enterolactone and enterodiol with prostatic tumor expression of NFκB, VEGF, and Ki67 among 147 patients with prostate cancer who participated in a presurgical trial of flaxseed supplementation (30 g/day) for ~30 days. Urinary enterolignans and tissue biomarkers were determined by high-performance liquid chromatography and immunohistochemistry, respectively. After supplementation, we observed significant correlations between intakes of plant lignan and urinary concentrations of total enterolignans (ρ=0.677, P<.0001), enterolactone (ρ=0.676, P<.0001), and enterodiol (ρ=0.628, P<.0001). Importantly, we observed that total urinary enterolignans and enterolactone were significantly and inversely correlated with Ki67 in the tumor tissue (ρ=-0.217, P=.011, and ρ=-0.230, P=.007, respectively), and a near-significant inverse association was observed for enterodiol (ρ=-0.159, P=.064). An inverse association was observed between enterolactone and VEGF (ρ=-0.143, P=.141), although this did not reach statistical significance. We did not observe an association between enterolignans and NFκB. In conclusion, flaxseed-derived enterolignans may hinder cancer cell proliferation via VEGF-associated pathways.

Increasing dwell time of mitomycin C in the upper tract with a reverse thermosensitive polymer.

UNLABELLED: Abstract Background and Purpose: Topical chemotherapy for urothelial cancer is dependent on adequate contact time of the chemotherapeutic agent with the urothelium. To date, there has not been a reliable method of maintaining this contact for renal or ureteral urothelial carcinoma. We evaluated the safety and feasibility of using a reverse thermosensitive polymer to improve dwell times of mitomycin C (MMC) in the upper tract. MATERIALS AND METHODS: Using a porcine model, four animals were treated ureteroscopically with both upper urinary tracts receiving MMC mixed with iodinated contrast. One additional animal received MMC percutaneously. The treatment side had ureteral outflow blocked with a reverse thermosensitive polymer plug. MMC dwell time was monitored fluoroscopically and intrarenal pressures measured. Two animals were euthanized immediately, and three animals were euthanized 5 days afterward. RESULTS: In control kidneys, drainage occurred at a mean of 5.3±0.58 minutes. Intrarenal pressures stayed fairly stable: 9.7±14.0 cm H20. In treatment kidneys, dwell time was extended to 60 minutes, when the polymer was washed out. Intrarenal pressures in the treatment kidneys peaked at 75.0±14.7 cm H20 and reached steady state at 60 cm H20. Pressures normalized after washout of the polymer with cool saline. Average washout time was 11.8±9.6 minutes. No histopathologic differences were seen between the control and treatment kidneys, or with immediate compared with delayed euthanasia. CONCLUSIONS: A reverse thermosensitive polymer can retain MMC in the upper urinary tract and appears to be safe from our examination of intrarenal pressures and histopathology. This technique may improve the efficacy of topical chemotherapy in the management of upper tract urothelial carcinoma.

Development and clinical validation of a real-time PCR assay for PITX2 DNA methylation to predict prostate-specific antigen recurrence in prostate cancer patients following radical prostatectomy.

Prostate cancer is the most common cancer among men. The prospective discrimination of aggressive and clinically insignificant tumors still poses a significant and, as yet, unsolved problem. PITX2 DNA methylation is a strong prognostic biomarker in prostate cancer. Recently, a diagnostic microarray for prostate cancer prognosis based on PITX2 methylation has been developed and validated. Because this microarray requires nonstandard laboratory equipment, its use in a diagnostic setting is limited. This study aimed to develop and validate an alternative quantitative real-time PCR assay for measuring PITX2 methylation that can easily be established in clinical laboratories, thereby facilitating the implementation of this biomarker in clinical practice. A methylation cut-off for patient stratification was established in a training cohort (n = 157) and validated in an independent test set (n = 523) of men treated with radical prostatectomy. In univariate Cox proportional hazards analysis, PITX2 hypermethylation was a significant predictor for biochemical recurrence (P < 0.001, hazard ratio = 2.614). Moreover, PITX2 hypermethylation added significant prognostic information (P = 0.003, hazard ratio = 1.814) to the Gleason score, pathological T stage, prostate-specific antigen, and surgical margins in a multivariate analysis. The clinical performance was particularly high in patients at intermediate risk (Gleason score of 7) and in samples containing high tumor cell content. This assay might aid in risk stratification and support the decision-making process when determining whether a patient might benefit from adjuvant treatment after radical prostatectomy.