Abstract Microsatellite instability-high (MSI-H) is a tumor-agnostic biomarker for immune checkpoint inhibitor therapy. However, MSI status is not routinely tested in prostate cancer, in part due to low prevalence and assay cost. As such, prediction of MSI status from hematoxylin and eosin (H&E) stained whole-slide images (WSIs) could identify prostate cancer patients most likely to benefit from confirmatory testing to evaluate their eligibility for immunotherapy and need for Lynch syndrome testing. Prostate biopsies and surgical resections from prostate cancer patients referred to our institution were analyzed. MSI status was determined by next-generation sequencing. Patients sequenced before a cutoff date formed an algorithm development set ( n = 4015, MSI-H 1.8%) and a paired validation set ( n = 173, MSI-H 19.7%) that consisted of two serial sections from each sample, one stained and scanned internally and the other at an external site. Patients sequenced after the cutoff date formed a temporally independent validation set ( n = 1350, MSI-H 2.3%). Attention-based multiple instance learning models were trained to predict MSI-H from H&E WSIs. The predictor achieved area under the receiver operating characteristic curve values of 0.78 (95% CI [0.69–0.86]), 0.72 (95% CI [0.63–0.81]), and 0.72 (95% CI [0.62–0.82]) on the internally prepared, externally prepared, and temporal validation sets, respectively, showing effective predictability and generalization to both external staining/scanning processes and temporally independent samples. While MSI-H status is significantly correlated with Gleason score, the model remained predictive within each Gleason score subgroup.
INTRODUCTION AND OBJECTIVE: Infectious complications following prostate biopsy remain a significant cause of patient morbidity driven by increasing antibiotic resistance. Fusion biopsy and transperineal biopsy are recently introduced biopsy techniques with increasing levels of adoption. We aim to evaluate effect of biopsy type with infectious complications. METHODS: The Michigan Urologic Surgery Improvement Collaborative (MUSIC) maintains a high quality, prospective prostate cancer registry with biopsy outcomes manually abstracted and reported at 30 days post-procedure. A review of all patients undergoing prostate biopsy from January 2012 – August 2019 was performed. Patient characteristics, biopsy-type, and 30-day complications were analyzed. Multivariable analysis was performed to assess risk factors for infectious complications and hospitalizations. RESULTS: A total of 66,525 biopsies were performed, of which 62,040 (93.26%) were transrectal ultrasound guided (TRUS), 1068 (1.61%) were transperineal (TP), 3322 (4.99%) were transrectal MRI-fusion (TRF), and 95 (0.14%) were transperineal MRI-fusion (TPF). In total, 1081 (1.62%) patients experienced an infectious-complication and 515 (0.77%) were hospitalized with for an infection-related indication. There were 83 (2.5%) men in the TRF biopsy group with an infectious complication compared to 989 (1.59%) in the TRUS, 9 (0.84%) in the TP and 0 (0%) in the TPF groups. When controlling for patient characteristics, TRF biopsy type was associated with increased odds of an infectious complication (OR 1.62, p<0.001) and infectious hospitalization (OR 2.16, p<0.001) when compared to TRUS patients. Total cores and diabetes were associated with an increased risk of an infectious complication. The transperineal approach and biopsies performed after the implementation of a state-wide antibiotic pathway designed to decrease these complications were less likely to result in an infection-related hospitalization. CONCLUSIONS: Transrectal fusion biopsy was associated with an increased risk of post-biopsy infectious complications and hospitalizations. Alternative biopsy techniques, including transperineal fusion biopsy, may mitigate this risk.Source of Funding: Blue Cross Blue Shield of Michigan as part of the BCBSM Value Partnership program
The use of near-infrared wavelengths for photoacoustic (PA) imaging takes advantage of the relatively low inherent absorption of tissues and has encouraged the development of agents which show high contrast in this range. Here, we describe the modification of a commercially available PA imaging system (Vevo LAZR, VisualSonics, Toronto) to take advantage of the 532nm and 1064nm wavelengths inherent in the generation of the currently tuneable range of 680 to 970nm and in the use of these two wavelengths to assess contrast agents. The photoacoustic imaging system generated light from a Nd/YAG laser modified to extract the 532 and 1064nm wavelengths in addition to its OPO-derived tuneable range (680 - 970 nm) and deliver this light through a fiber integrated into a linear array transducer (LZ400, VisualSonics). Gold nanorods (UT Austin), carbon nanotubes (Stanford U), DyLight 550 (Thermo Fisher) and blood were imaged in a phantom (PE20 tubing) and in a hindlimb subcutaneous tumor in vivo to determine their photoacoustic signal intensity at all wavelengths. In the phantom and in vivo, all agents caused an enhancement of the photoacoustic signal at their respective peak absorbance wavelengths. These results show that the 532nm and 1064nm wavelengths could prove useful in biomedical imaging due to the contrast agents customized for them. The 1064nm wavelength in particular has the advantage of having very low generation of endogenous signal in vivo, making agents tuned to this wavelength ideal for targeted contrast imaging.
The hepsin gene encodes a type II transmembrane serine protease. Previous studies have shown the overexpression of hepsin in prostate cancer, and the dysregulation of hepsin promotes cancer cell proliferation, migration, and metastasis in vitro and in vivo. The review incorporated with our work showed that hepsin expression levels were specifically increased in prostate cancer, and higher expression in metastatic tumors than in primary tumors was also observed. Moreover, increased expression was associated with poor outcomes for patients with prostate cancer. Using in silico protein-protein interaction prediction, mechanistic analysis showed that hepsin interacted with eight other oncogenic proteins, whose expression was significantly correlated with hepsin expression in prostate cancer. The oncogenic functions of hepsin are mainly linked to proteolytic activities that disrupt epithelial integrity and regulatorily interact with other genes to influence cell-proliferation, EMT/metastasis, inflammatory, and tyrosine-kinase-signaling pathways. Moreover, genomic amplifications of hepsin, not deletions or other alterations, were significantly associated with prostate cancer metastasis. Targeting hepsin using a specific inhibitor or antibodies significantly attenuates its oncogenic behaviors. Therefore, hepsin could be a novel biomarker and therapeutic target for prostate cancer.
The immunization status and frequency of contraindications to immunization were studied in 446 children attending the paediatric clinic of a teaching hospital in south India. In all, 27% of the children were up to date in their immunizations, 19% had a contraindication, and 57% required and could safely be given immunizations. A policy of offering immunizations in paediatric clinics to all who require them and who do not have a contraindication would result in protection of a significant number of unimmunized children.
Centrifugal pumps are increasingly used for extracorporeal membrane oxygenation (ECMO) rather than roller pumps. However, shear forces induced by these types of continuousflow pumps are associated with acquired von Willebrand factor deficiency and bleeding complications. This study was undertaken to compare adverse bleeding complications with the use of centrifugal and roller pumps in patients on prolonged ECMO support. The records of all adult ECMO patients from June 2002 to 2013 were retrospectively reviewed using the University of Michigan Health System database and the Extracorporeal Life Support Organization registry, focusing on patients supported for at least 5 days. Ninety-five ECMO patients met criteria for inclusion (48 roller vs. 47 centrifugal pump). Indications included pulmonary (79%), cardiac (15%), and extracorporeal cardiopulmonary resuscitation (6%), without significant difference between the two groups. Despite lower heparin anticoagulation (10.9 vs. 13.7 IU/kg/hr) with centrifugal pumps, there was a higher incidence of nonsurgical bleeding (gastrointestinal, pulmonary, and neurological) in centrifugal pump patients (26.1 vs. 9.0 events/1,000 patient-days, p = 0.024). In conclusion, in our historical comparison, despite reduced anticoagulation, ECMO support using centrifugal pumps was associated with a higher incidence of nonsurgical bleeding. The mechanisms behind this are multifactorial and require further investigation
To report the independent prognostic impact of the new prostate cancer grade-grouping system in a large external validation cohort of patients treated with radical prostatectomy (RP).Between 1994 and 2013, 3 694 consecutive men were treated with RP at a single institution. To investigate the performance of and validate the grade-grouping system, biochemical recurrence-free survival (bRFS) rates were assessed using Kaplan-Meier tests, Cox-regression modelling, and discriminatory comparison analyses. Separate analyses were performed based on biopsy and RP grade.The median follow-up was 52.7 months. The 5-year actuarial bRFS for biopsy grade groups 1-5 were 94.2%, 89.2%, 73.1%, 63.1%, and 54.7%, respectively (P < 0.001). Similarly, the 5-year actuarial bRFS based on RP grade groups was 96.1%, 93.0%, 74.0%, 64.4%, and 49.9% for grade groups 1-5, respectively (P < 0.001). The adjusted hazard ratios for bRFS relative to biopsy grade group 1 were 1.98, 4.20, 5.57, and 9.32 for groups 2, 3, 4, and 5, respectively (P < 0.001), and for RP grade groups were 2.09, 5.27, 5.86, and 10.42 (P < 0.001). The five-grade-group system had a higher prognostic discrimination compared with the commonly used three-tier system (Gleason score 6 vs 7 vs 8-10).In an independent surgical cohort, we have validated the prognostic benefit of the new prostate cancer grade-grouping system for bRFS, and shown that the benefit is maintained after adjusting for important clinicopathological variables. The greater predictive accuracy of the new system will improve risk stratification in the clinical setting and aid in patient counselling.
