Physicochemical degradation of calcium magnesium phosphate (stanfieldite) based bone replacement materials and the effect on their cytocompatibility.

Regenerative bone implants should be completely replaced by new bone within a period of time corresponding to the growth rate of native bone. To meet this requirement, suitable biomaterials must be biodegradable and promote osteogenesis. The combination of slowly degrading but osteoconductive calcium phosphates (CPs) with rapidly degrading and mechanically more resilient magnesium phosphates represents a promising material class for this purpose. In order to create the best possible conditions for optimal implant integration, microporous calcium magnesium phosphate (CMP) cements were processed using 3D powder printing. This technique enables the production of a defect-adapted implant with an optimal fit and a high degree of open porosity to promote bone ingrowth. Four different compositions of 3D printed CMP ceramics were investigated with regard to essential properties of bone implants, including chemical composition, porosity, microstructure, mechanical strength, and cytocompatibility. The ceramics consisted of farringtonite (Mg3(PO4)2) and stanfieldite (Ca4Mg5(PO4)6), with either struvite (NH4MgPO4·6H2O) or newberyite (MgHPO4·3H2O) and brushite (CaHPO4·2H2O) as additional phases. The CMP materials showed open porosities between 13 and 28% and compressive strengths between 11 and 17 MPa, which was significantly higher, as compared with clinically established CP. The cytocompatibility was evaluated with the human fetal osteoblast cell line hFOB 1.19 and was proven to be equal or to even exceed that of tricalcium phosphate. Furthermore, a release of 4-8 mg magnesium and phosphate ions per mg scaffold material could be determined for CMPs over a period of 21 d. In the case of struvite containing CMPs the chemical dissolution of the cement matrix was combined with a physical degradation, which resulted in a mass loss of up to 3.1 wt%. In addition to its beneficial physical and biological properties, the proven continuous chemical degradation and bioactivity in the form of CP precipitation indicate an enhanced bone regeneration potential of CMPs.

Immediate radiotherapy versus observation in patients with node-positive prostate cancer after radical prostatectomy.

BACKGROUND: The optimal management of node-positive (pN1) prostate cancer following radical prostatectomy (RP) remains uncertain. Despite randomized evidence, utilization of immediate, life-long androgen deprivation therapy (ADT) remains poor, and recent trials of early salvage radiotherapy included only a minority of pN1 patients. We therefore emulated a hypothetical pragmatic trial of adjuvant radiotherapy versus observation in men with pN1 prostate cancer. METHODS: Using the RADICALS-RT trial to inform the design of a hypothetical trial, we identified men aged 50-69 years with pT2-3 Rany pN1 M0, pre-treatment PSA < 50 ng/mL prostate cancer in the NCDB from 2006 to 2015 treated with 60-72 Gy of adjuvant RT (aRT) ± ADT within 26 weeks of RP or observation. After estimating a propensity score for receipt of aRT, we estimated absolute and relative treatment effects using stabilized inverse probability of treatment (sIPW) re-weighting. RESULTS: In total, 3510 patients were included in the study, of whom 587 (17%) received aRT (73% with concurrent ADT). Median follow-up was 40.0 -months, during which 333 deaths occurred. After sIPW re-weighting, baseline characteristics were well-balanced. Adjusted overall survival (OS) was 93% versus 89% at 5-years and 82% versus 79% at 7-years for aRT versus observation (p = 0.11). In IPW-reweighted Cox regression, aRT was associated with a lower risk of all-cause mortality (ACM) than observation, but this did not reach statistical significance (HR 0.70 p = 0.06). In analyses examining heterogeneity of treatment effects, aRT was associated with improved ACM only for men with Gleason 8-10 disease (HR 0.59, p = 0.01), ≥2 positive LNs (HR 0.49, p = 0.04 for 2 positive LNs; HR 0.42, p = 0.01 for ≥3 positive LNs), or negative surgical margins (HR 0.50, p = 0.02). CONCLUSIONS: In observational analyses designed to emulate a hypothetical target trial of aRT versus observation in pN1 prostate cancer, aRT was associated with improved OS only for men with Gleason 8-10 disease, ≥2 positive LNs, or negative surgical margins.

How many cores are enough? Optimizing the transperineal prostate biopsy template.

INTRODUCTION AND OBJECTIVE: Most urologists use a 10-12 core template during transrectal ultrasound guided prostate biopsy (TRUS-B). A similar consensus template does not exist for transperineal prostate biopsy (TP-B) including the optimal number and location of biopsy cores. We examined our institutional cohort to develop an optimal systematic template for TP-B. METHODS: We prospectively monitored our first 200 consecutive free-hand TP-B. These included men who were biopsy naïve (n = 117), had elevated PSA with prior negative biopsy (n = 18), and men on active surveillance (n = 65). All men underwent a 20 core TP-B with each core placed in a separate specimen container. This allowed the 20-core TP-B to be easily broken down as though fewer cores had been taken in each patient. Ten, 12, and 16 core templates were designed a priori and compared within each patient to the 20 core template. The highest Grade Group (GG) at pathologic analysis was assigned to each biopsy. Primary outcome was detection of clinically significant prostate cancer, defined as ≥GG2. Secondary outcome was detection of GG1 prostate cancer. We performed sub-group analyses of biopsy naïve men and biopsy naïve men stratified by PSA density (<0.15 vs. ≥0.15 ng/mL/cc). An historic institutional cohort of 10-12 core TRUS-B (n = 170) was used to compare prostate cancer detection between techniques. P value of ≤0.05 was considered statistically significant. RESULTS: Clinically significant cancers were detected in 98 men (49%) using a 20 core TP-B technique. Had we sampled fewer cores we would have identified clinically significant cancers in 93 (47%, 16 core), 91 (46%, 12 core), and 82 (41%, 10 core) men. More clinically significant cancers were detected by the 20 core template compared to the 10 core template for both the whole cohort (49% vs. 41%, P = 0.02) and the biopsy naïve subset (48% vs. 40%, P = 0.05). Additional cores did not result in an increased detection of GG1 cancers (20-core: 35% vs. 10-core: 44%, P = 0.09). Less than one quarter of biopsy naïve men with a PSA density <0.15 were found to have clinically significant cancers. More clinically significant cancers were detected in the 12-core TP-B cohort compared to the 12-core TRUS-B series (46% vs. 38%, P < 0.001). CONCLUSIONS: A 20 core TP-B systematic biopsy template detected a greater number of clinically significant prostate cancers compared to a 10 core TP template. Cancer detection was similar for 12, 16, and 20 core templates. Higher core numbers did not result in greater detection of GG1 tumors reflecting increased detection of concomitant ≥GG2 with greater sampling. We propose a minimum 12 core systematic biopsy template for men undergoing TP-B.

Complete response of penile mycosis fungoides with systemic brentuximab therapy.

Mycosis fungoides with penile involvement is extremely rare. Previous reports have shown successful treatment with imiquimod or a combination of beam radiation and chemotherapy. We present a patient with mycosis fungoides and penile involvement. The penile lesions were initially treated with topical imiquimod; however, he developed worsening glandular lesions and discharge. Therefore the treatment was discontinued. Subsequent treatment with brentuximab (anti-CD30) targeted therapy resulted in complete resolution of the penile lesions. To our knowledge, this represents the first case of a complete penile mycosis fungoides response to brentuximab therapy. Brentuximab may be considered for refractory penile mycoses fungoides.

Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant.

RATIONALE: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. OBJECTIVES: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. METHODS: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. MEASUREMENTS AND MAIN RESULTS: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. CONCLUSIONS: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

Ex Vivo Lung Perfusion Model to Study Pulmonary Tissue Extracellular Microvesicle Profiles.

BACKGROUND: Extracellular microvesicles (EVs) are being increasingly studied for their diagnostic potential. We investigated the feasibility of studying the kinetics and tissue-specific profiles of pulmonary EVs in the context of ex vivo lung perfusion (EVLP) used for salvaging marginal lungs for transplantation. METHODS: Perfusate from six marginal donor lungs placed on EVLP was collected at the following time points: 0, 10, and 60 minutes after and after perfusate exchange with Steen Solution; 120 and 180 minutes. Three lungs were successfully recovered for transplantation (transplant group), and three were not recoverable (nontransplant group). Perfusate EVs were isolated using methods of size exclusion chromatography, ultrafiltration, and ultracentrifugation. EVs were analyzed on NanoSight nanoparticle detector for quantity, size distribution, and surface expression of pulmonary tissue-specific markers. EV cargoes were profiled using mass spectrometry, reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis. RESULTS: Time course analysis showed EV presence by 10-minute time point. EV median size was smaller in the transplant group (165 nm versus 212 nm, p = 0.04). EV cargo analysis on Western blot analysis, RT-PCR, and NanoSight showed contribution from monocytes (CD14), endothelium (platelet endothelial cell adhesion molecule 1), and pulmonary parenchyma (epithelial cell adhesion molecule) into the perfusate total EV pool. Mass spectrometry showed differences in the EV protein cargoes of the transplant group versus the nontransplant group. CONCLUSIONS: EVLP system provides a platform to understand the kinetics of pulmonary EVs in an isolated fashion. Donor lung recovery may be associated with changes in EV size distribution and proteomic profiles. Pulmonary tissue-specific EV profiling using the EVLP system may provide insights into EV contribution to pulmonary pathologic processes.

Massive donor transfusion potentially increases recipient mortality after lung transplantation.

OBJECTIVE: Donor blood transfusion has been identified as a potential risk factor for primary graft dysfunction and by extension early mortality. We sought to define the contributing risk of donor transfusion on early mortality for lung transplant. METHODS: Donor and recipient data were abstracted from the Organ Procurement and Transplantation Network database updated through June 30, 2014, which included 86,398 potential donors and 16,255 transplants. Using the United Network for Organ Sharing 4-level designation of transfusion (no blood, 1-5 units, 6-10 units, and >10 units, massive), we analyzed all-cause mortality at 30-days with the use of logistic regression adjusted for confounders (ischemic time, donor age, recipient diagnosis, lung allocation score and recipient age, and recipient body mass index). Secondary analyses assessed 90-day and 1-year mortality and hospital length of stay. RESULTS: Of the 16,255 recipients transplanted, 8835 (54.35%) donors received at least one transfusion. Among those transfused, 1016 (6.25%) received a massive transfusion, defined as >10 units. Those donors with massive transfusion were most commonly young trauma patients. After adjustment for confounding variables, donor massive transfusion was associated significantly with an increased risk in 30-day (P = .03) and 90-day recipient mortality (P = .01) but not 1-year mortality (P = .09). There was no significant difference in recipient length of stay or hospital-free days with respect to donor transfusion. CONCLUSIONS: Massive donor blood transfusion (>10 units) was associated with early recipient mortality after lung transplantation. Conversely, submassive donor transfusion was not associated with increased recipient mortality. The mechanism of increased early mortality in recipients of lungs from massively transfused donors is unclear and needs further study but is consistent with excess mortality seen with primary graft dysfunction in the first 90 days posttransplant.