Circulating tumor DNA and tissue complementarily detect genomic alterations in metastatic hormone-sensitive prostate cancer.

The clinical utility of circulating tumor DNA (ctDNA) in hormone-sensitive prostate cancer (HSPC) remains inadequately elucidated. This study presents the largest real-world cohort to conduct a concordance analysis between ctDNA and tissue-based genomic profiling in HSPC patients. The findings reveal diminished ctDNA abundance in cases with low tumor burden and demonstrate an increased concordance rate between ctDNA and tissue along with the progression of disease burden. Notably, a substantial number of exclusive genomic alterations (GAs) were identified either in ctDNA or tissue in high-volume metastatic disease. Integrating tissue and ctDNA analysis identified specific gene alterations (BRCA1, BRCA2, CDK12, TP53, PTEN, or RB1) associated with a shorter time to the progression to castration-resistant prostate cancer (CRPC), with an escalated CRPC risk correlated with cumulative GAs. This multicenter, real-world investigation underscores the complementary role of ctDNA and tissue in detecting clinically pertinent GAs, highlighting their potential integration into clinical practice for advanced prostate cancer management.

Autologous Endothelial Progenitor Cells and Bioactive Factors Improve Bladder Regeneration.

Insufficient vascularization is still a challenge that impedes bladder tissue engineering and results in unsatisfied smooth muscle regeneration. Since bladder regeneration is a complex articulated process, the aim of this study is to investigate whether combining multiple pathways by exploiting a combination of biomaterials, cells, and bioactive factors, contributes to the improvements of smooth muscle regeneration and vascularization in tissue-engineered bladder. Autologous endothelial progenitor cells (EPCs) and bladder smooth muscle cells (BSMCs) are cultured and incorporated into our previously prepared porcine bladder acellular matrix (BAM) for bladder augmentation in rabbits. Simultaneously, exogenous vascular endothelial growth factor (VEGF) and platelet-derived growth factor BB (PDGF-BB) mixed with Matrigel were injected around the implanted cells-BAM complex. In the results, compared with control rabbits received bladder augmentation with porcine BAM seeded with BSMCs, the experimental animals showed significantly improved smooth muscle regeneration and vascularization, along with more excellent functional recovery of tissue-engineered bladder, due to the additional combination of autologous EPCs and bioactive factors, including VEGF and PDGF-BB. Furthermore, cell tracking suggested that the seeded EPCs could be directly involved in neovascularization. Therefore, it may be an effective method to combine multiple pathways for tissue-engineering urinary bladder.

Concordance and Clinical Significance of Genomic Alterations in Progressive Tumor Tissue and Matched Circulating Tumor DNA in Aggressive-variant Prostate Cancer.

Sequencing of circulating tumor DNA (ctDNA) is a minimally invasive approach to reveal the genomic alterations of cancer; however, its comparison with sequencing of tumor tissue has not been well documented in real-world patients with aggressive-variant prostate cancer (AVPC). Concordance of genomic alterations was assessed between progressive tumor tissue and matched ctDNA by next-generation sequencing for 63 patients with AVPC. Associations of genomic alterations with progression-free survival (PFS) and overall survival (OS) were investigated using Kaplan-Meier and Cox regression analyses. A total of 161 somatic mutations (SMs) and 84 copy-number variants (CNVs) were detected in tumors, of which 97 were also found in ctDNA, giving concordance of 39.6% (97/245) across all SMs and CNVs, 49.7% for SMs only and 20.2% for CNVs only. Across all patients with AVPC, chemotherapy was associated with significantly longer median PFS (6 vs. 0.75 months, P = 0.001) and OS (11 vs. 8 months, P < 0.001) than next-generation hormonal therapy (NHT). Among types of chemotherapy, additional platinum-based chemotherapy was associated with significantly longer median PFS and OS than docetaxel only in patients with TP53, RB1, or PTEN alterations, and in those with ctDNA% ≥ 13.5%. The concordance analysis first provides evidence for combining the sequencing of ctDNA and tumor tissue in real-world patients with AVPC. Chemotherapy is associated with significantly better survival than NHT, and the benefit of additional platinum-based chemotherapy may depend on the presence of alterations in TP53, RB1, or PTEN and on a sufficiently high proportion of ctDNA in patients with AVPC. SIGNIFICANCE: AVPC is a highly malignant and heterogeneous disease. Sequencing of ctDNA is a minimally invasive approach to reveal genomic alterations. On the basis of the current real-world study, we found ctDNA does not fully recapitulate the landscape of genomic alterations from progressive tumor tissue in AVPC. We also revealed AVPC can benefit from chemotherapy, especially platinum-based regimens. TP53/RB1/PTEN alterations in ctDNA or tumor tissue could be biomarkers for platinum-based chemotherapy in this setting.

Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer.

Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1+ myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1+ myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-ß signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1+ myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC.

Perioperative change of circulating tumor cells in cytoreductive radical prostatectomy for oligometastatic hormone-sensitive prostate cancer: the preliminary safety evidence from long-term oncologic outcomes.

Surgical manipulation has a risk of triggering the shedding of circulating tumor cells (CTCs) in patients with malignancies, However, perioperative change of circulating tumor cells in cytoreductive radical prostatectomy (CRP) for patients with oligometastatic hormone-sensitive prostate cancer (omHSPC) has not yet been well documented. This study aimed to assess whether CRP is a safe procedure for patients with omHSPC by monitoring the perioperative change of CTCs and investigating its impact on long-term oncologic outcomes. We have observed a significant decrease between the median CTC counts before and after surgery (6 vs. 4, p = 0.026). Comparing preoperative and postoperative CTC levels, seven patients increased (CTC increase group), one did not change and nineteen decreased (CTC non-increase group). PSA response rates in CTC increase group were lower than those in CTC non-increase group (73.0% vs 99.8%, p = 0.162), and nadir PSA was higher in CTC increase group (0.043 vs 0.003, p = 0.072). The CTC increase was positively correlated with the nadir PSA (r = 0.386, p = 0.047). The median follow-up period was 71.6 months, we found that there was no significant difference in clinical-pathological, operative variables or long-term oncologic outcomes between perioperative CTC increase and non-increase groups. In the entire cohort, the CTC level significantly decreased after surgery. There was no significant differences in long-term oncologic outcomes between the CTC increase and non-increase groups, implying that CRP potentially represents a safe procedure for the treatment of patients with omHSPC. The results need to be confirmed in a prospective large-scale clinical trial.

Highly stable and recoverable humidity sensor using fluorescent quantum dot film.

Fluorescent sensors are resistant to electromagnetic interference and are electrically insulated, allowing for highly accurate measurements. Quantum dots (QDs) serve as outstanding sensing materials owing to the unique optical properties such as tunable photoluminescence (PL), excellent visible light activity, and high chemical and physical stability. In this paper, we develop an optical humidity sensor based on a QDs nanocomposite film. The film is made of polyvinyl alcohol (PVA), SiO2 microsphere (SM), and QDs through the layer-by-layer self-assembly method. The mechanism of humidity detection is moisture-induced quenching of the QDs fluorescence intensity. The results reveal that our sensor shows a good linear response to relative humidity in the range of 5% to 97%, a fast response-recovery time of 25 s and 20 s, and good repeatability for more than 50 cycles as well as high stability for over 180 days. Possessing the remarkable property, optical humidity sensors are envisaged for great potential applications in environmental monitoring.

Microfiber-directed reversible assembly of Au nanoparticles for SERS detection of pollutants.

Surface-enhanced Raman scattering (SERS) spectroscopy has attracted tremendous interest as a highly sensitive label-free tool to detect pollutants in aqueous environments. However, the high cost and poor reusability of conventional SERS substrates restrict their further applications in rapid and reproducible pollutant detection. Here, we report a reliable optical manipulation method to achieve rapid photothermal self-assembly of Au nanoparticles (AuNPs) in water within 30 s by a tapered optical fiber, which is utilized for highly sensitive SERS substrate preparation. The results show that the SERS substrate achieves low detection limits of 10-9 mol/L with an enhancement factor (EF) of 106 for chemical pollutants solutions, including thiram, pyrene, and rhodamine 6G. The SERS enhancement effect based on assembled AuNPs was more than 20 times that based on a gold colloid solution. As a result, the smart reversible assembly of AuNPs exhibits switchable plasmonic coupling for tuning SERS activity, which is promising for the application of SERS-based sensors and environmental pollutant detection.

PVA-SM microstructure enhanced ratiometric fluorescence probe for formaldehyde detection in solution and gas.

Formaldehyde (FA) is one of the most common pollutants, which has tremendous harm to humans and environment. In this work, 4-amino-3-pentene-2-one (Fluoral-p) and SiO2 coated quantum dot (QD@SiO2) were combined to implement a new ratiometric fluorescence probe QD@SiO2-Fluoral-p for FA detection. In addition, by utilization of polyvinyl alcohol (PVA) and SiO2 microsphere (SM), a kind of PVA-SM microstructure was assembled with QD@SiO2-Fluoral-p to composite a signal enhanced sensing film. The QD@SiO2-Fluoral-p exhibited good response to 0-400 mg/L FA solution and an enhancement around 15 folds was realized after introducing PVA-SM. In both situations, the probe showed linear relationship to FA concentration (CFA), with detection limits of 14 and 0.5 mg/L, respectively. Also, the sensing film showed a good linear response to FA gas in the range of 0 to 2 ppm, with a detection limit 0.03 ppm. As a result, the PVA-SM enhanced ratiometric fluorescence probe features high sensitivity, low detection limit, good selectivity, as well as portable, which can serve as a useful tool for investigating FA in solution and gas at room temperature.

Identifying the Candidates Who Will Benefit From Extended Pelvic Lymph Node Dissection at Radical Prostatectomy Among Patients With Prostate Cancer.

PURPOSE: The therapeutic effect of extended pelvic lymph node dissection (PLND) in prostate cancer (PCa) patients is still controversial. The aim of this study was to identify the PCa patients who may benefit from extended PLND based on the 2012 Briganti nomogram. MATERIALS AND METHODS: PCa patients who underwent radical prostatectomy (RP) plus PLND between 2010 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The probability of lymph node invasion (LNI), determined using the 2012 Briganti nomogram, was used to stratify the patients. The endpoints were overall survival (OS) and cancer-specific survival (CSS). Propensity score matching (PSM) was performed to account for potential differences between patients with and without extended PLND. Univariable and multivariable Cox regression was used to analyze the association between the number of removed nodes (NRN) and survival. Kaplan-Meier analysis was performed to estimate OS and CSS. Extended PLND was defined as NRN >75th percentile. RESULTS: A total of 27,690 patients were included in the study. NRN was not an independent predictor of OS (p = 0.564). However, in patients with probability of LNI ≥37, multivariable analyses showed that increased NRN was associated with improved OS (hazard ratio [HR] = 0.963; p = 0.002). The 5-y OS rate was significantly higher for patients with NRN ≥12 than those with NRN <12 (94.9% vs. 91.9%, respectively; p = 0.015). In the PSM cohort, among patients with probability of LNI ≥37, multivariable analyses showed that increased NRN was associated with improved OS (HR = 0.961; p = 0.004). In addition, the 5-y OS rate was significantly higher for patients with NRN ≥12 than those with NRN <12 (94.9% vs. 89.8%, respectively; p = 0.002). However, NRN was not an independent predictor of CSS in any LNI risk subgroup (all p >0.05). CONCLUSION: Extensive PLND might be associated with improved survival in PCa patients with a high risk of LNI, which supports the use of extended PLND in highly selected PCa patients. The results need to be validated in prospective studies with long-term follow-up.

Clinical Significance of Mesenchymal Circulating Tumor Cells in Patients With Oligometastatic Hormone-Sensitive Prostate Cancer Who Underwent Cytoreductive Radical Prostatectomy.

PURPOSE: Growing evidence shows that circulating tumor cells (CTCs) become more aggressive after the epithelial-mesenchymal transition (EMT), though the clinical significance of CTCs undergoing EMT in oligometastatic hormone-sensitive prostate cancer (omHSPC) patients has not yet been reported. Accordingly, the aim of this study was to detect the CTC level and investigate the clinical significance of mesenchymal CTCs in omHSPC patients who underwent cytoreductive radical prostatectomy (CRP). MATERIALS AND METHODS: Blood samples were drawn from 54 omHSPC patients who underwent CRP. The CanPatrol CTC enrichment technique was applied to isolate and identify different phenotypes of CTCs, which were classified as epithelial (E-CTCs), mesenchymal (M-CTCs), or biphenotypic epithelial/mesenchymal (Bi-CTCs). Univariable and multivariable Cox regression analyses were employed to investigate potential prognostic factors for metastatic castration-resistant prostate cancer (mCRPC)-free survival and cancer-specific survival (CSS). The prognostic value of CTCs for CSS and mCRPC-free survival was assessed using time-dependent receiver operating characteristic (ROC) curves and Kaplan-Meier analysis. RESULTS: CTCs were detected in 51 of 54 patients (94%). E-CTC, M-CTC, and Bi-CTC detection rates were 56%, 67%, and 85%, respectively. A positive correlation was found between the M-CTC count and number of bone metastases (p = 0.012). Time-dependent ROC analysis showed that the M-CTC count had higher predictive power than E-CTC or Bi-CTC for mCRPC-free survival (3-year area under the curve [AUC] values: 0.64, 0.60, and 0.61) and CSS (3-year AUC: 0.86, 0.58, and 0.67). Additionally, time-dependent ROC analysis revealed total CTCs (T-CTCs) ≥5 and M-CTCs ≥2 to be the cutoff points with optimal specificity and sensitivity. Based on multivariable Cox regression, T-CTC and M-CTC counts were both independently associated with CSS and mCRPC-free survival (all p < 0.05), though E-CTCs and Bi-CTCs had no significant prognostic value (all p > 0.05). Patients with T-CTC ≥5 or M-CTC ≥2 had significantly worse mCRPC-free survival and CSS than those with T-CTC<5 or M-CTC<2 (all p < 0.05) after CRP. CONCLUSION: CTC quantification and phenotype characterization provide prognostic information, and M-CTCs can be used as a novel biomarker for omHSPC patients who undergo CRP. The results need to be validated in prospective studies.

[Relationship between lower limb alignment distribution and short-term clinical results after primary total knee arthroplasty in patients with varying degrees of knee varus].

OBJECTIVE: To analyze the relationship between the distribution of lower limb alignment and short term clinical efficacy in patients with varus-type osteoarthritis after primary total knee arthroplasty (TKA). METHODS: From December 2016 to March 2018, 87 patients (101 knees) with knee osteoarthritis were treated with the first total knee arthroplasty by the same medical group, including 21 males(25 knees) and 66 females(76 knees), ranging in age from 51 to 85 years old, with a mean of (67.6±7.0) years old. According to the difference of hip knee ankle angle (HKA) after total knee arthroplasty, the patients were divided into 4 groups:neutral position group (group A), -3°≤HKA≤3°, 50 knees;slight varus group (group B), 3°< HKA<6°, 20 knees;severe varus group (group C), HKA≥6°, 20 knees;valgus group (group D), HKA<- 3°, 11 knees. The preoperative sex, age, body mass index, operative side, preoperative and postoperative knee joint activity, HSS score, KSS clinical and functional score were compared among the 4 groups, and the relationship between the force line distribution of femoral and tibial prosthesis and the recent clinical effect was compared. RESULTS: All the patients were followed up with a mean duration of(18.4±4.0) months. The range of motion of knee joint, HSS and KSS scores at the latest follow-up after operation in the 4 groups were higher than those before operation, and the difference was statistically significant (P<0.001). There were significant differences in HSS and KSS scores among the 4 groups at the latest follow up (P<0.05);and the results in group A were better than those in group C and group D (P<0.05);the results in group B were better than those in group C and group D (P< 0.05);there was no significant difference between group A and group B or group C and group D(P>0.05). There was no significant difference in knee joint activity among the 4 groups. The score of femoral prosthesis force line within ±3°was better than that of the other group (P<0.05), and the score of tibia prosthesis force line had no significant difference between within ±3° group and other group (P>0.05). CONCLUSION: The short term clinical efficacy of patients with knee varus osteoarthritis after primary total knee arthroplasty is related to the distribution of lower limbs alignment. The short-term clinical efficacy of slight inversion position can be similar to that of neutral position. The force line distribution of femoral prosthesis is related to the short term clinical efficacy after primary knee arthroplasty.

[Effect of surgeon's handedness on distribution of prosthesis during primary total knee arthroplasty].

OBJECTIVE: To evaluate the effect of the surgeon's handedness on the distribution of prosthesis during primary total knee arthroplasty (TKA). METHODS: A retrospective analysis was performed on 86 patients (100 knees) with primary TKA completed by the same right-handed surgeon between December 2016 and December 2018, including 72 cases of single knee and 14 of bilateral knees. The patients were divided into dominant group (right side) and non-dominant group (left side) according to the operating position of the surgeon and each group had 50 knees. There was no significant difference in gender, age, body mass index, disease duration, clinical diagnosis, preoperative Hospital for Special Surgery (HSS) score, and other general data between the two groups ( P>0.05). The operation time and complications were recorded in both groups. The function of knee was evaluated by HSS score. Hip-knee-ankle angle (HKA), mechanical lateral distal femoral angle (mLDFA), and mechanical medial proximal tibial angle (mMPTA) were measured by using X-ray film of full-length lower extremity before TKA and at 2 weeks after TKA that were used to evaluate the coronal position of the prosthesis. Posterior distal femoral angle (PDFA) and posterior proximal tibial angle (PPTA) were measured by using lateral X-ray films at 3 months after operation that were used to evaluate the sagittal position of the prosthesis. RESULTS: There was no significant difference in operation time between the two groups ( t=-1.128, P=0.262). One case of posterior tibial artery thrombosis occurred in the dominant group, and 1 case of poor healing of the incision occurred in each of the dominant group and the non-dominant group. Patients in both groups were followed up 12-34 months with an average of 22.0 months. The HSS scores at last follow-up were 87.2±4.3 in the dominant group and 86.8±5.0 in the non-dominant group. There was no significant difference between the two groups ( t=0.471, P=0.639). No complications such as periprosthetic infection, prosthetic loosening, or periprosthetic fracture occurred during follow-up. There was no significant difference in the HKA, mLDFA, and mMPTA between the two groups before and after operation ( P>0.05). The differences in the incidence of sagittal femoral prosthesis malposition and PDFA between the two groups were significant ( P<0.05); however, there was no significant difference in the PPTA, the rate of femoral prosthesis distributed in the neutral position, the incidence of over-flexed femoral prosthesis, and the incidence of anterior femoral notch ( P>0.05). CONCLUSION: The surgeon's handedness is one of the factors affecting the placement of the sagittal femoral prosthesis in primary TKA. The incidence of sagittal femoral prosthesis malposition could increase when the surgeon performs on the non-dominant side.