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The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies., Author(s): Christopher Abbosh [1]; Nicolai J. Birkbak [1, 2]; Gareth A. Wilson [1, 2]; Mariam Jamal-Hanjani [1]; Tudor Constantin [3]; Raheleh Salari [3]; John Le Quesne [4]; David A. Moore [...]

PURPOSE: To develop and validate a cross-ancestry integrated risk score (caIRS) that combines a cross-ancestry polygenic risk score (caPRS) with a clinical estimator for breast cancer (BC) risk. We hypothesized that the caIRS is a better predictor of BC risk than clinical risk factors across diverse ancestry groups. METHODS: We used diverse retrospective cohort data with longitudinal follow-up to develop a caPRS and integrate it with the Tyrer-Cuzick (T-C) clinical model. We tested the association between the caIRS and BC risk in two validation cohorts including > 130,000 women. We compared model discrimination for 5-year and remaining lifetime BC risk between the caIRS and T-C and assessed how the caIRS would affect screening in the clinic. RESULTS: The caIRS outperformed T-C alone for all populations tested in both validation cohorts and contributed significantly to risk prediction beyond T-C. The area under the receiver operating characteristic curve improved from 0.57 to 0.65, and the odds ratio per standard deviation increased from 1.35 (95% CI, 1.27 to 1.43) to 1.79 (95% CI, 1.70 to 1.88) in validation cohort 1 with similar improvements observed in validation cohort 2. We observed the largest gain in positive predictive value using the caIRS in Black/African American women across both validation cohorts, with an approximately two-fold increase and an equivalent negative predictive value as the T-C. In a multivariate, age-adjusted logistic regression model including both caIRS and T-C, caIRS remained significant, indicating that caIRS provides information over T-C alone. CONCLUSION: Adding a caPRS to the T-C model improves BC risk stratification for women of multiple ancestries, which could have implications for screening recommendations and prevention. Cross-ancestry integrated score improves breast cancer risk prediction for women of diverse ancestries. [ABSTRACT FROM AUTHOR]

Background: MRI-guided transurethral ultrasound ablation (TULSA) is under investigation for whole-gland ablation of low- and intermediate-risk prostate cancer. The ideal method for post-TULSA bladder drainage through postoperative suprapubic tube (SPT) vs indwelling urethral catheter (UC) has not been established. The objective of this study was to evaluate urinary outcomes after whole-gland TULSA, comparing postoperative SPT with UC. Materials and Methods: Two-institution retrospective analysis of whole-gland TULSA for men with grade group 1 and 2 prostate cancer. One institution placed SPT at the time of TULSA with clamp trials (day 10) and removal once voiding. The second placed UC until void trial (day 7). Outcomes included the International Prostate Symptom Score (IPSS), urinary bother score, catheter reinsertion, stricture, clean intermittent catheterization (CIC), and incontinence. Results: Forty-five patients (median age 67) were analyzed. The UC cohort (N = 26) was older (p = 0.007) than the SPT cohort (N = 19) but with similar baseline prostate volumes, IPSS, and urinary bother scores. Patients receiving UC had fewer days with catheter (p = 0.013). Although UC patients suffered more lower urinary tract symptoms at 1-month post-TULSA, there was no significant difference between IPSS scores at baseline and 6 months after surgery regardless of urinary management strategy, although the UC group noted significantly decreased urinary bother. Rates of infection were similar between groups. Six strictures were observed overall, with more in the SPT group, although the difference was not significant (4/19 [21.1%] SPT; 2/26 [7.7%] UC). At 6 months, incontinence rates were low and similar between groups (2/19 [10.5%] SPT; 4/26 [15.4%] UC) and only one patient (UC) required CIC. Conclusions: Our overall findings suggest that SPT and UC are both acceptable options for postoperative bladder drainage after whole-gland TULSA, with statistically similar rates of urinary complications but a slightly different side effect profile. [ABSTRACT FROM AUTHOR]

Author(s): Christopher Abbosh; Nicolai J. Birkbak; Gareth A. Wilson; Mariam Jamal-Hanjani; Tudor Constantin; Raheleh Salari; John Le Quesne; David A. Moore; Selvaraju Veeriah; Rachel Rosenthal; Teresa Marafioti; Eser Kirkizlar; Thomas [...]

We describe the common presenting signs and symptoms, treatment modalities, and outcomes of acutely presenting scrotal pyoceles. We conducted a retrospective chart review of all adult patients treated for ultrasound-confirmed scrotal pyoceles between 2010 and 2020 at two sites within the [redacted]. Vitals at presentation, microbiology, and inpatient courses including antibiotic treatment and surgical procedures were collected. A total of 360 scrotal ultrasounds were reviewed identifying 15 patients with pyoceles, 11 patients presenting to the emergency department and 4 hospitalized patients. The most common chief complaint was testicular pain (67%). Only seven patients (47%) met SIRS criteria upon presentation. All patients were initially treated with broad-spectrum antibiotics and observation; 11 (73%) responded to this management alone, while four patients (27%) required surgical drainage due to persistent infection. No patients contracted Fournier's gangrene. This study reports the largest published database of scrotal pyoceles to date and describes our clinical approach to management. While pyoceles have traditionally been treated aggressively with surgical drainage, this case series suggests that most patients improve with broad-spectrum antibiotic treatment and observation alone, requiring surgical drainage if infection persists. Future investigations including multi-institutional data will be necessary to validate our institution's approach. [ABSTRACT FROM AUTHOR]

The performance robustness of time of arrival (TOA) and time difference of arrival (TDOA) is evaluated when measurement variances are not accurately known or are approximated. If the actual variances are applied, then TOA and TDOA are known to have equal performance. However, if suboptimal weighting matrices are applied either due to inaccurate knowledge of measurement error statistics or for simplified implementations in practice, there are performance losses proportional to the number of ranging sources.

The technique discussed herein may be used to position a range of wireless devices that require location information when in inclement urban conditions, including PDA's, laptops, cellular phones, asset-tracking devices and radios for emergency response personnel. We make use of synchronization signals that are part of the standard for Television set forth by the Advanced Television Systems Committee. Consequently, the technique described herein requires no changes to the television broadcast stations. The signal can accommodate robust indoor positioning where the Global Positioning System (GPS) fails, since the television synchronization signals typically have a power advantage over GPS of more than 40 dB. In addition, the effects of multipath are substantially mitigated since the signals have a bandwidth of roughly 6 MHz, and substantially superior geometry for triangulating lateral position to that which GPS can typically provide in inclement environments. A wide range of VHF and UHF frequencies have been allocated to television stations; consequently, there is redundancy built into the system to protect against deep fades on particular channels. In addition, unlike GPS, the synch signals are not affected by transmitter Doppler, ionospheric propagation delays, or data that is modulated onto the signals. In overview, the technology exploits the considerable Digital TV infrastructure to achieve more reliable, accurate and rapid positioning than can be achieved with existing technologies. Index Terms--Digital Television, location, positioning, rosum.

According to the current international guidelines, high‐risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE‐Japan project includes a large‐scale patient‐screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE‐Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients. [ABSTRACT FROM AUTHOR]

Objective: To retrospectively evaluate the outcomes of immediate artificial urinary sphincter (AUS) reactivation in patients after urethral cuff replacement. It is common practice to delay reactivation of an AUS for four to six weeks following surgery to replace a failed urethral cuff. This is due to concerns about local tissue edema risking obstruction and concerns for urethral erosion. Despite these concerns, there are no published data to support this practice.Methods: Retrospective chart review of single surgeon procedures performed from 2005-2020. Patients with urethral cuff replacement for recurrent stress incontinence due to compression or mechanical failure were included.Results: Thirty-four patients were identified who had immediate reactivation of the AUS following urethral cuff exchange. Thirty of these patients (88.2%) had radical prostatectomy and five patients also underwent further radiation therapy (14.7%). At 6 months follow-up, there was no reported events of erosion. Likewise, 32/34 (94%) of patients had no complications and reported expected urinary function of the AUS. Urinary retention was not observed. One patient required further re-exploration for a complication within his AUS system (2.9%), and another was ultimately unsatisfied with their unchanged baseline continence despite a fully functioning AUS (2.9%).Conclusion: In this series, we observe that immediate reactivation of the AUS after urethral cuff exchange is a safe and reasonable management approach. Limitations of this analysis include a single institution, retrospective study. However, early AUS reactivation after device revision has not been reported in the literature and warrants further investigation given the impact on patient quality of life. [ABSTRACT FROM AUTHOR]

Adoption of the prostatic urethral lift (PUL) as a treatment for benign prostatic hyperplasia highlights the importance of training residents with novel technology without compromising patient care. This study examines the effect of resident involvement during PUL on patient and procedural outcomes. Retrospective chart review was conducted on all consecutive PUL cases performed by a single academic urologist between October 2017 and November 2019. Trainees in post-graduate year (PGY) 1–3 are considered junior residents, while those in PGY 4–6 are senior residents. The International Prostate Symptom Score (IPSS) and quality of life (QOL) scores were used to measure outcomes. Simple and mixed-effects linear regression models were used to compare differences. There were 110 patients with a median age of 66.4 years. Residents were involved in 73 cases (66.4%), and senior residents were involved in 31 of those cases. Resident involvement was not associated with adverse perioperative outcomes with respect to the number of implants fired, the percentage of implants successfully placed, or the postoperative catheterization rate. After adjustment for confounding factors, junior residents were associated with significantly longer case length compared to the attending alone (+12.6 min, P = 0.003) but senior residents were not (+2.4 min, P = 0.59). IPSS and QOL scores were not significantly affected by resident involvement (P = 0.12 and P = 0.21, respectively). The presence of surgeons-in-training, particularly those in the early stages, prolongs PUL case length but does not appear to have an adverse impact on patient outcomes. [ABSTRACT FROM AUTHOR]

Objective: To examine the long-term efficacy of prostatic urethral lift (PUL) for treating men, with or without an obstructive median lobe (OML), who suffer from lower urinary tract symptoms attributed to benign prostatic hyperplasia.Materials and Methods: A retrospective review was performed on all consecutive PUL cases with or without OML from October 2017 to November 2019 by a single academic surgeon. Outcomes were measured using the International Prostate Symptoms Survey (IPSS) with quality of life (QoL) scores. Comparative testing and mixed-effects linear regression analysis were utilized with significance set at α = 0.05 and performed with Stata (College Station, TX).Results: A total of 110 PUL procedures were performed on 106 patients (4 repeat surgeries) with a median age of 66.5 (interquartile range: 60.4-73.7). Twenty-three patients (21.7%) had an OML. Following PUL, patients in both groups showed significant improvements in IPSS (P <.001) and QoL (P <.001) scores. When stratifying by OML and controlling for confounding, IPSS scores in both groups displayed statistically significant improvement at follow-up visits, with no statistically significant intergroup difference (P = .32). The same held true for QoL improvements, with no statistically significant difference between groups (P = .18). The presence of an OML resulted in minimal effects on perioperative outcomes and complications but required significantly more implants (P = .008).Conclusion: PUL is a minimally invasive procedure effective at reducing lower urinary tract symptoms and improving the lives of men with benign prostatic hyperplasia without incurring risks of serious complications. These improvements were equivalent and upheld in patients who presented with OML. [ABSTRACT FROM AUTHOR]

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE‐Japan including three clinical trials. The GALAXY study is a prospectively conducted large‐scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high‐risk stage II or low‐risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double‐blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor–positive status in the GALAXY study. Therefore, CIRCULATE‐Japan encompasses both "de‐escalation" and "escalation" trials for ctDNA‐negative and ‐positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA‐guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management. [ABSTRACT FROM AUTHOR]

Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4–8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS) to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF) cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos provides insight into the cytogenetic mechanisms underlying their formation and the consequences for human fertility. [ABSTRACT FROM AUTHOR]

Objective: Analyze the economic value of replacing conventional fetal aneuploidy screening approaches with non-invasive prenatal testing (NIPT) in the general pregnancy population. Methods: Using decision-analysis modeling, we compared conventional screening to NIPT with cell-free DNA (cfDNA) analysis in the annual US pregnancy population. Sensitivity and specificity for fetal aneuploidies, trisomy 21, trisomy 18, trisomy 13, and monosomy X, were estimated using published data and modeling of both first- and second trimester screening. Costs were assigned for each prenatal test component and for an affected birth. The overall cost to the healthcare system considered screening costs, the number of aneuploid cases detected, invasive procedures performed, procedure-related euploid losses, and affected pregnancies averted. Sensitivity analyses evaluated the effect of variation in parameters. Costs were reported in 2014 US Dollars. Results: Replacing conventional screening with NIPT would reduce healthcare costs if it can be provided for $744 or less in the general pregnancy population. The most influential variables were timing of screening entry, screening costs, and pregnancy termination rates. Of the 13,176 affected pregnancies undergoing screening, NIPT detected 96.5% (12,717/13,176) of cases, compared with 85.9% (11,314/13,176) by conventional approaches. NIPT reduced invasive procedures by 60.0%, with NIPT and conventional methods resulting in 24,596 and 61,430 invasive procedures, respectively. The number of procedure-related euploid fetal losses was reduced by 73.5% (194/264) in the general screening population. Conclusion: Based on our analysis, universal application of NIPT would increase fetal aneuploidy detection rates and can be economically justified. Offering this testing to all pregnant women is associated with substantial prenatal healthcare benefits. [ABSTRACT FROM AUTHOR]